Hypoglycaemia in Clinical DiabetesSecond Edition
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Hypoglycaemia in Clinical DiabetesSecond EditionEdited byBrian M. FrierThe Royal Infirmary of Edinburgh, Scotland, UKMiles FisherGlasgow Royal Infirmary, Scotland, UK
ContentsPreface ixContributors xi1 Normal Glucose Metabolism and Responses to Hypoglycaemia 1Ian A. Macdonald and Paromita King2 Symptoms of Hypoglycaemia and Effects on Mental Performanceand Emotions 25Ian J. Deary3 Frequency, Causes and Risk Factors for Hypoglycaemia in Type 1Diabetes 49Mark W.J. Strachan4 Nocturnal Hypoglycaemia 83Simon R. Heller5 Moderators, Monitoring and Management of Hypoglycaemia 101Tristan Richardson and David Kerr6 Counterregulatory Deficiencies in Diabetes 121David Kerr and Tristan Richardson7 Impaired Awareness of Hypoglycaemia 141Brian M. Frier8 Risks of Strict Glycaemic Control 171Stephanie A. Amiel9 Hypoglycaemia in Children with Diabetes 191Krystyna A. Matyka10 Hypoglycaemia in Pregnancy 217Ann E. Gold and Donald W.M. Pearson11 Hypoglycaemia in Type 2 Diabetes and in Elderly People 239Nicola N. Zammitt and Brian M. Frier12 Mortality, Cardiovascular Morbidity and Possible Effects ofHypoglycaemia on Diabetic Complications 265Miles Fisher and Simon R. Heller
viii CONTENTS13 Long-term Effects of Hypoglycaemia on Cognitive Function and theBrain in Diabetes 285Petros Perros and Ian J. Deary14 Living with Hypoglycaemia 309Brian M. FrierIndex 333
PrefaceIn the second edition of this book, we have continued to emphasise the clinical significanceof hypoglycaemia to the person who has diabetes, particularly when receiving treatmentwith insulin. Since the first edition of the book was published in 1999, new therapies haveemerged, including new insulin analogues and inhaled insulin, and monitoring systems arenow available that can provide continuous recording of blood glucose. However, far fromminimising the risk of hypoglycaemia in clinical practice, the newer treatments have beenshown to be as liable to cause hypoglycaemia as before, while continuous blood glucosemonitoring has revealed that this side-effect of insulin therapy is even more common thanwas believed previously. The frequency of severe hypoglycaemia in vulnerable groups suchas children and elderly people receiving insulin therapy is unacceptably high, and presentspotentially serious risks to health as well as diminishing their quality of life. Much scientificresearch in recent years has focused on the effects of hypoglycaemia on the brain, providinga greater understanding of the protean effects of this metabolic abnormality. New data andconcepts have been incorporated in this edition, particularly where these are of importanceto clinical practice.In updating and revising this book about hypoglycaemia, particular emphasis has beengiven to the risk factors for hypoglycaemia and how these may be reduced or avoided. Newchapters have been included to discuss recognised moderators of hypoglycaemia and the roleof new glucose monitoring systems, to address the increasing problem of hypoglycaemia inpeople with type 2 diabetes and the elderly person, and to acknowledge the major importanceof nocturnal hypoglycaemia, which is frequently not identified in clinical practice but canhave serious consequences, not only in its immediate morbidity, but also in promoting thedevelopment of the acquired syndromes of hypoglycaemia.We are grateful for the expert assistance and support of the colleagues who havecontributed chapters, some of whom are new as authors for this edition. All have skillfullyhighlighted the relevance of the enhancement of scientific knowledge in this field to theeveryday management of diabetes, which we hope will assist all members of the diabetesteam in their efforts to prevent and manage the extremely common but unwanted scourgethat is hypoglycaemia.Brian M. FrierMiles Fisher
ContributorsProfessor Stephanie A. Amiel, R.D. Lawrence Professor of Diabetes, Departmentof Medicine, King’s College Hospital, Bessemer Road, London, SE5 9PJ (e-mail:email@example.com)Professor Ian J. Deary, Department of Psychology, University of Edinburgh, 7 GeorgeSquare, Edinburgh, EH8 9JZ (e-mail: firstname.lastname@example.org)Dr Miles Fisher, Consultant Physician, Glasgow Royal Infirmary, Glasgow, G4 0SF (e-mail:email@example.com)Professor Brian M. Frier, Consultant Physician, Department of Diabetes, Royal Infirmary,51 Little France Crescent, Edinburgh, EH16 4SA (e-mail: firstname.lastname@example.org)Dr Ann E. Gold, Consultant Physician, Wards 27 and 28, Aberdeen Royal Infirmary,Foresterhill, Aberdeen, AB25 2ZN (e-mail: email@example.com)Professor Simon R. Heller, Professor of Clinical Diabetes, Clinical Sciences Centre, Depart-ment of Diabetes & Endocrinology, Northern General Hospital, Herries Road, Sheffield, S57AU (e-mail: firstname.lastname@example.org)Dr David Kerr, Consultant Physician, The Royal Bournemouth Hospital, Castle Lane East,Bournemouth, BH7 7DW (e-mail: David.Kerr@rbch.nhs.uk)Dr Paromita King, Consultant Physician, Jenny O’Neill Diabetes Centre, Derbyshire RoyalInfirmary, London Road, Derby, DE1 2QY (e-mail: Paru.King@derbyhospitals.nhs.uk)Professor Ian A. Macdonald, Professor of Metabolic Physiology, Department of Physi-ology and Pharmacology, Medical School, Queen’s Medical Centre, Nottingham, NG7 2UH(e-mail: Ian.Macdonald@nottingham.ac.uk)Dr Krystyna A. Matyka, Senior Lecturer in Paediatrics, University of Warwick MedicalSchool, Division of Clinical Sciences, CSB Research Wing, UHCW Trust, Clifford BridgeRoad, Coventry, CV2 2DX (e-mail: K.A.Matyka@warwick.ac.uk)Dr Donald W.M. Pearson, Consultant Physician, Aberdeen Royal Infirmary, Foresterhill,Aberdeen, AB25 2ZN (e-mail: Dwm.Pearson@arh.grampian.scot.nhs.uk)Dr Petros Perros, Consultant Endocrinologist, Ward 15, Freeman Hospital, Freeman Road,Newcastle-Upon-Tyne, NE7 7DN (e-mail: Petros.Perros@ncl.ac.uk)Dr Tristan Richardson, Consultant Physician, Bournemouth Diabetes and EndocrineCentre, The Royal Bournemouth Hospital, Castle Lane East, Bournemouth, BH7 7DW(e-mail: Tristan.Richardson@rbch.nhs.uk)
xii CONTRIBUTORSDr Mark W.J. Strachan, Consultant Physician, Metabolic Unit, Western General Hospital,Crewe Road, Edinburgh, EH4 2XU (e-mail: email@example.com)Dr Nicola N. Zammitt, Specialist Registrar, Department of Diabetes, Royal Infirmaryof Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA (e-mail: firstname.lastname@example.org)
2 NORMAL GLUCOSE METABOLISM AND RESPONSESInsulin and glucagon are the two hormones controlling glucose homeostasis, and thereforethe mechanisms enabling the ‘rules’ to be followed. The most important processes governedby these hormones are:• Glycogen synthesis and breakdown (glycogenolysis): Glycogen, a carbohydrate, is anenergy source stored in the liver and skeletal muscle. Liver glycogen is broken downto provide glucose for all tissues, whereas the breakdown of muscle glycogen results inlactate formation.• Gluconeogenesis: This is the production of glucose in the liver from precursors: glycerol,lactate and amino acids (in particular alanine). The process can also occur in the kidneys,but this site is not important under physiological conditions.• Glucose uptake and metabolism (glycolysis) by skeletal muscle and adipose tissue.The actions of insulin and glucagon are summarised in Boxes 1.1 and 1.2. Insulin is ananabolic hormone, reducing glucose output by the liver (hepatic glucose output), increasingthe uptake of glucose by muscle and adipose tissue (increasing peripheral uptake) andincreasing protein and fat formation. Glucagon opposes the actions of insulin in the liver.Thus insulin tends to reduce, and glucagon to increase, blood glucose concentrations.Box 1.1 Actions of insulinLiver↑ Glycogen synthesis (↑ glycogen synthetase activity)↑ Glycolysis↑ Lipid formation↑ Protein formation↓ Glycogenolysis (↓ phosphorylase activity)↓ Gluconeogenesis↓ Ketone formationMuscle↑ Uptake of glucoseamino acidsketonepotassium↑ Glycolysis↑ Synthesis of glycogenprotein↓ Protein catabolism↓ Release of amino acidsAdipose tissue↑ Uptake glucosepotassiumStorage of triglyceride
NORMAL GLUCOSE HOMEOSTASIS 3Box 1.2 Actions of glucagonLiver↑ Glycogenolysis↑ Gluconeogenesis↑ Extraction of alanine↑ KetogenesisNo significant peripheral actionThe metabolic effects of insulin and glucagon and their relationship to glucose homeostasisare best considered in relationship to fasting and the postprandial state (Siegal and Kreisberg,1975). In both these situations it is the relative and not absolute concentrations of thesehormones that are important.Fasting (Figure 1.1a)During fasting, insulin concentrations are reduced and glucagon increased, which main-tains blood glucose concentrations in accordance with rule 1 above. The net effect is toreduce peripheral glucose utilisation, to increase hepatic glucose production and to providenon-glucose fuels for tissues not entirely dependent on glucose. After a short (for exampleovernight) fast, glucose production needs to be 5–6 g/h to maintain blood glucose concen-trations, with the brain using 80% of this. Glycogenolysis provides 60–80% and gluconeo-genesis 20–40% of the required glucose. In prolonged fasts, glycogen becomes depletedand glucose production is primarily from gluconeogenesis, with an increasing proportionfrom the kidney compared to the liver. In extreme situations renal gluconeogenesis cancontribute as much as 45% of glucose production. Thus glycogen is the short term or ‘emer-gency’ fuel source (rule 2), with gluconeogenesis predominating during more prolongedfasts. The following metabolic alterations enable this increase in glucose productionto occur:• Muscle: Glucose uptake and oxidative metabolism are reduced and fatty acid oxidationincreased. Amino acids are released.• Adipose tissue: There are reductions in glucose uptake and triglyceride storage. Theincrease in the activity of the enzyme hormone-sensitive lipase results in hydrolysisof triglyceride to glycerol (a gluconeogenic precursor) and fatty acids, which can bemetabolised.• Liver: Increased cAMP concentrations result in increased glycogenolysis and gluconeo-genesis thus increasing hepatic glucose output. The uptake of gluconeogenic precursors(i.e. amino acids, glycerol, lactate and pyruvate) is also increased. Ketone bodies areproduced in the liver from fatty acids. This process is normally inhibited by insulin andstimulated by glucagon, thus the hormonal changes during fasting lead to an increase inketone production. Fatty acids are also a metabolic fuel used by the liver and provide asource of energy for the reactions involved in gluconeogenesis.
4 NORMAL GLUCOSE METABOLISM AND RESPONSESAmino acidsFree FAGlycogenGlucoseGlycerolHepatic glucoseoutputFFA, TG,lipoproteinKetonesMuscleGlucoseFree FATriglycerideAdipose TissueGlycogenGlucoseGlycerolHepatic glucoseoutputFFA, TG,LiverFASTING POST PRANDIALTGFA GlycerolphosphateFA GlycerolphosphateGlycerol TriglycerideKetonesglucagon, insulin Insulin, glucagonlactate GlycogenProteinAmino acids ProteinGlucose GlycogenlactateAmino acidsFAFA(a) (b)Figure 1.1 Metabolic pathways for glucose homeostasis in muscle, adipose tissue and liver duringfasting (left) and postprandially (right). FA = fatty acids; TG = triglyceride (associated CO2 productionexcluded for clarity)The reduced insulin : glucagon ratio favours a catabolic state, but the effect on fatmetabolism is greater than protein, and thus muscle is relatively preserved (rule 4). Theseadaptations meant that not only did hunter-gatherers have sufficient muscle power topursue their next meal, but also that brain function was optimally maintained to help themdo this.
EFFECTS OF GLUCOSE DEPRIVATION 5Fed state (Figure 1.1b)In the fed state, in accordance with the rules of the metabolic game, excess food is stored asglycogen, protein and fat (rule 3). The rise in glucose concentrations results in an increasein insulin and reduction in glucagon secretion. This balance favours glucose utilisation,reduction of glucose production and increases glycogen, triglyceride and protein formation.The following changes enable these processes to occur:• Muscle: Insulin increases glucose transport, oxidative metabolism and glycogen synthesis.Amino acid release is inhibited and protein synthesis is increased.• Adipose tissue: In the fat cells, glucose transport is increased, while lipolysis is inhibited.At the same time the enzyme lipoprotein lipase, located in the capillaries, is activatedand causes triglyceride to be broken down to fatty acids and glycerol. The fatty acidsare taken up into the fat cells and re-esterified to triglyceride (using glycerol phosphatederived from glucose) before being stored.• Liver: Glucose uptake is increased in proportion to plasma glucose, a process which doesnot need insulin. However, insulin does decrease cAMP concentrations, which results in anincrease in glycogen synthesis and the inhibition of glycogenolysis and gluconeogenesis.These effects ‘retain’ glucose in the liver and reduce hepatic glucose output.This complex interplay between insulin and glucagon maintains euglycaemia and enablesthe rules of the metabolic game to be followed, ensuring not only the survival of thehunter-gatherer, but also of modern humans.EFFECTS OF GLUCOSE DEPRIVATION ON CENTRAL NERVOUSSYSTEM METABOLISMThe brain constitutes only 2% of body weight, but consumes 20% of the body’s oxygenand receives 15% of its cardiac output (Sokaloff, 1989). It is almost totally dependenton carbohydrate as a fuel and since it cannot store or synthesise glucose, depends ona continuous supply from circulating blood. The brain contains the enzymes needed tometabolise fuels other than glucose such as lactate, ketones and amino acids, but underphysiological conditions their use is limited by insufficient quantities in the blood or slowrates of transport across the blood-brain barrier. When arterial blood glucose falls below3 mmol/l, cerebral metabolism and function decline.Metabolism of glucose by the brain releases energy, and also generates neurotransmitterssuch as gamma amino butyric acid (GABA) and acetylcholine, together with phospholipidsneeded for cell membrane synthesis. When blood glucose concentration falls, changes inthe synthesis of these products may occur within minutes because of reduced glucosemetabolism, which can alter cerebral function. This is likely to be a factor in producingthe subtle changes in cerebral function detectable at blood glucose concentrations as highas 3 mmol/l, which is not sufficiently low to cause a major depletion in ATP or creatinephosphate, the brain’s two main sources of energy (McCall, 1993).
6 NORMAL GLUCOSE METABOLISM AND RESPONSESIsotope techniques and Positron Emission Tomography (PET) allow the study ofmetabolism in different parts of the brain and show regional variations in metabolismduring hypoglycaemia. The neocortex, hippocampus, hypothalamus and cerebellum are mostsensitive to hypoglycaemia, whereas metabolism is relatively preserved in the thalamusand brainstem. Changes in cerebral function are initially reversible, but during prolongedsevere hypoglycaemia, general energy failure (due to the depletion of ATP and creatinephosphate) can cause permanent cerebral damage. Pathologically this is caused by selectiveneuronal necrosis most likely due to ‘excitotoxin’ damage. Local energy failure induces theintrasynaptic release of glutamate or aspartate, and failure of reuptake of the neurotrans-mitters increases their concentrations. This leads to the activation of N-methyl-D-aspartate(NMDA) receptors causing cerebral damage. One study in rats has shown that an experi-mental compound called AP7, which blocks the NMDA receptor, can prevent 90% of thecerebral damage associated with severe hypoglycaemia (Wieloch, 1985). In humans withfatal hypoglycaemia, protracted neuroglycopenia causes laminar necrosis in the cerebralcortex and diffuse demyelination. Regional differences in neuronal necrosis are seen, withthe basal ganglia and hippocampus being sensitive, but the hypothalamus and cerebellumbeing relatively spared (Auer and Siesjö, 1988; Sieber and Traysman, 1992).The brain is very sensitive to acute hypoglycaemia, but can adapt to chronic fuel depri-vation. For example, during starvation, it can metabolise ketones for up to 60% of itsenergy requirements (Owen et al., 1967). Glucose transport can also be increased in theface of hypoglycaemia. Normally, glucose is transported into tissues using proteins calledglucose transporters (GLUT) (Bell et al., 1990). This transport occurs down a concentrationgradient faster than it would by simple diffusion and does not require energy (facilitateddiffusion). There are several of these transporters, with GLUT 1 being responsible fortransporting glucose across the blood-brain barrier and GLUT 3 for transporting glucoseinto neurones (Figure 1.2). Chronic hypoglycaemia in animals (McCall et al., 1986) andin humans (Boyle et al., 1995) increases cerebral glucose uptake, which is thought to bepromoted by an increase in the production and action of GLUT 1 protein. It has not beenFigure 1.2 Transport of glucose into the brain across the blood–brain barrier
COUNTERREGULATION DURING HYPOGLYCAEMIA 7established whether this adaptation is of major benefit in protecting brain function duringhypoglycaemia.COUNTERREGULATION DURING HYPOGLYCAEMIAThe potentially serious effects of hypoglycaemia on cerebral function mean that not onlyare stable blood glucose concentrations maintained under physiological conditions, but alsoif hypoglycaemia occurs, mechanisms have developed to combat it. In clinical practice, theprincipal causes of hypoglycaemia are iatrogenic (as side-effects of insulin and sulphony-lureas used to treat diabetes) and excessive alcohol consumption. Insulin secreting tumours(such as insulinoma) are rare. The mechanisms that correct hypoglycaemia are called coun-terregulation, because the hormones involved oppose the action of insulin and therefore arethe counterregulatory hormones. The processes of counterregulation were identified in themid 1970s and early 1980s, using either a bolus injection or continuous infusion of insulinto induce hypoglycaemia (Cryer, 1981; Gerich, 1988). The response to the bolus injectionof 0.1 U/kg insulin in a normal subject is shown in Figure 1.3. Blood glucose concentrationsdecline within minutes of the administration of insulin and reach a nadir after 20–30 minutes,then gradually rise to near normal by two hours after the insulin was administered. The factFigure 1.3 (a) Glucose and (b) insulin concentrations after intravenous injection of insulin 0.1 U/kgat time 0. Reproduced from Garber et al. (1976) by permission of the Journal of Clinical Investigation
8 NORMAL GLUCOSE METABOLISM AND RESPONSESthat blood glucose starts to rise when plasma insulin concentrations are still ten times thebaseline values means that it is not simply the reduction in insulin that reverses hypogly-caemia, but active counterregulation must also occur. Many hormones are released whenblood glucose is lowered (see below), but glucagon, the catecholamines, growth hormoneand cortisol are regarded as being the most important.Several studies have determined the relative importance of these hormones by producingisolated deficiencies of each hormone (by blocking its release or action) and assessingthe subsequent response to administration of insulin. These studies are exemplified inFigure 1.4 which assesses the relative importance of glucagon, adrenaline (epinephrine) andgrowth hormone in the counterregulation of short term hypoglycaemia. Somatostatin infusionblocks glucagon and growth hormone secretion and significantly impairs glucose recovery(Figure 1.4a). If growth hormone is replaced in the same model to produce isolated glucagondeficiency (Figure 1.4b), and glucagon replaced to produce isolated growth hormone defi-ciency (Figure 1.4c), it is clear that it is glucagon and not growth hormone that is responsiblefor acute counterregulation. Combined alpha and beta adrenoceptor blockade using phento-lamine and propranolol infusions or adrenalectomy (Figure 1.4d), can be used to evaluatethe role of the catecholamines. These and other studies demonstrate that glucagon is themost important counterregulatory hormone whereas catecholamines provide a backup ifglucagon is deficient (for example in type 1 diabetes, see Chapters 6 and 7). Cortisol andFigure 1.4 Glucose recovery from acute hypoglycaemia. Glucose concentration following an intra-venous injection of insulin of 0.05 U/kg at time 0; after (a) saline infusion (continuous line) andsomatostatin, (b) somatostatin and growth hormone (GH), (c) somatostatin and glucagon, (d) combinedalpha and beta blockade with phentolamine and propranolol infusions or adrenalectomy, (e) somato-statin with alpha and beta blockade, and (f) somatostatin in adrenalectomised patients. Saline infu-sion = continuous lines; experimental study = broken lines. Reproduced from Cryer (1981) courtesyof the American Diabetes Association (epinephrine = adrenaline)
COUNTERREGULATION DURING HYPOGLYCAEMIA 9growth hormone are important only in prolonged hypoglycaemia. Therefore if glucagonand catecholamines are both deficient, as in longstanding type 1 diabetes, counterregulationis seriously compromised, and the individual is defenceless against acute hypoglycaemia(Cryer, 1981).Glucagon and catecholamines increase glycogenolysis and stimulate gluconeogenesis.Catecholamines also reduce glucose utilisation peripherally and inhibit insulin secretion.Cortisol and growth hormone increase gluconeogenesis and reduce glucose utilisation. Therole of the other hormones (see below) in counterregulation is unclear, but they are unlikelyto make a significant contribution. Finally, there is evidence that during profound hypo-glycaemia (blood glucose below 1.7 mmol/l), hepatic glucose output is stimulated directly,although the mechanism is unknown. This is termed hepatic autoregulation.The depth, as well as the duration, of hypoglycaemia is important in determining themagnitude of the counterregulatory hormone response. Studies using ‘hyperinsulinaemicclamps’ show a hierarchical response of hormone production. In this technique, insulin isinfused at a constant rate and a glucose infusion rate varied to maintain blood glucoseconcentrations within ±0 2mmol/l of target concentrations. This permits the controlledevaluation of the counterregulatory hormone response at varying degrees of hypoglycaemia.It also demonstrates that glucagon, catecholamines and growth hormone start to be secretedat a blood glucose concentration of 3.5–3.7 mmol/l, with cortisol produced at a lower glucoseof 3.0 mmol/l (Mitrakou et al., 1991). The counterregulatory response is initiated beforeimpairment in cerebral function commences, usually at a blood glucose concentration ofapproximately 3.0 mmol/l (Heller and Macdonald, 1996).The magnitude of the hormonal response also depends on the length of the hypogly-caemic episode. The counterregulatory hormonal response commences up to 20 minutesafter hypoglycaemia is achieved and continues to rise for 60 minutes (Kerr et al., 1989).In contrast, this response is attenuated as a result of a previous episode of hypoglycaemia(within a few days) (reviewed by Heller and Macdonald, 1996) and even by prolongedexercise the day before hypoglycaemia is induced. Galassetti et al. (2001) showed that innon-diabetic subjects three hours of moderate intensity exercise the previous day markedlydecreased the counterregulatory response to hypoglycaemia induced by the infusion ofinsulin, and that the reduced counterregulatory response was more marked in men thanin women.Although the primary role of the counterregulatory hormones is on glucose metabolism,any effects on fatty acid utilisation can have an indirect effect on blood glucose. Thus,the increase in plasma epinephrine (adrenaline) (and activation of the sympathetic nervoussystem) that is seen in hypoglycaemia can stimulate lipolysis of triglyceride in adipose tissueand muscle and release fatty acids which can be used as an alternative fuel to glucose, makingmore glucose available for the CNS. Enoksson et al. (2003) demonstrated that patients withtype 1 diabetes, who had lower plasma epinephrine responses to hypoglycaemia than non-diabetic controls, also had reduced rates of lipolysis in adipose tissue and skeletal muscle,making them more dependent on glucose as a fuel and therefore at risk of developing a moresevere hypoglycaemia.The complex counterregulatory and homeostatic mechanisms described above are thoughtto be mostly under the control of the central nervous system. Evidence for this comesfrom studies in dogs, where glucose was infused into the carotid and vertebral arteries tomaintain euglycaemia in the brain. Despite peripheral hypoglycaemia, glucagon did notincrease and responses of the other counterregulatory hormones were blunted. This, and
10 NORMAL GLUCOSE METABOLISM AND RESPONSESother studies in rats, led to the hypothesis that the ventromedial nucleus of the hypothalamus(VMH), which does not have a blood–brain barrier, acts as a glucose-sensor and co-ordinatescounterregulation (Borg et al., 1997). However, evidence exists that other parts of the brainmay also be involved in mediating counterregulation.It is now clear that glucose-sensing neurones can involve either glucokinase or ATP-sensitive K+channels (Levin et al., 2004). In rats, the VMH has ATP-sensitive K+channelswhich seem to be involved in the counterregulatory responses to hypoglycaemia, as injectionof the sulphonylurea, glibenclamide, directly into the VMH suppressed hormonal responsesto systemic hypoglycaemia (Evans et al., 2004).The existence of hepatic autoregulation suggests that some peripheral control should exist.Studies producing central euglycaemia and hepatic portal venous hypoglycaemia in dogshave provided evidence for hepatic glucose sensors and suggest that these sensors, as wellas those in the brain, are important in the regulation of glucose (Hamilton-Wessler et al.,1994). However, this topic is somewhat controversial and more recent studies on dogs havefailed to demonstrate an effect of hepatic sensory nerves on the responses to hypoglycaemia(Jackson et al., 2000). Moreover, studies in humans by Heptulla et al. (2001) showedthat providing glucose orally rather than intravenously during a hypoglycaemic hyperin-sulinaemic clamp actually enhanced the counterregulatory hormone responses rather thanreduced them.HORMONAL CHANGES DURING HYPOGLYCAEMIAHypoglycaemia induces the secretion of various hormones, some of which are responsible forcounterregulation, many of the physiological changes that occur as a consequence of loweringblood glucose and contribute to symptom generation (see Chapter 2), The stimulation of theautonomic nervous system is central to many of these changes.Activation of the Autonomic Nervous SystemThe autonomic nervous system comprises sympathetic and parasympathetic components(Figure 1.5). Fibres from the sympathetic division leave the spinal cord with the ventral rootsfrom the first thoracic to the third or fourth lumbar nerves to synapse in the sympatheticchain or visceral ganglia, and the long postganglionic fibres are incorporated in somaticnerves. The parasympathetic pathways originate in the nuclei of cranial nerves III, VII, IXand X, and travel with the vagus nerve. A second component, the sacral outflow, suppliesthe pelvic viscera via the pelvic branches of the second to fourth spinal nerves. The gangliain both cases are located near the organs supplied, and the postganglionic neurones aretherefore short.Selective activation of both components of the autonomic system occurs during hypo-glycaemia. The sympathetic nervous system in particular is responsible for many of thephysiological changes during hypoglycaemia and the evidence for its activation can beobtained indirectly by observing functional changes such as cardiovascular responses (consid-ered below), measuring plasma catecholamines which gives a general index of sympatheticactivation, or by directly recording sympathetic activity.
HORMONAL CHANGES DURING HYPOGLYCAEMIA 11Figure 1.5 Anatomy of the autonomic nervous system. Pre = preganglionic neurones; post = post-ganglionic neurones; RC = ramus communicansDirect recordings are possible from sympathetic nerves supplying skeletal muscle and skin.Sympathetic neural activity in skeletal muscle involves vasoconstrictor fibres which innervateblood vessels and are involved in controlling blood pressure. During hypoglycaemia (inducedby insulin), the frequency and amplitude of muscle sympathetic activity are increased asblood glucose falls, with an increase in activity eight minutes after insulin is injectedintravenously, peaking at 25–30 minutes coincident with the glucose nadir, and persisting
12 NORMAL GLUCOSE METABOLISM AND RESPONSESFigure 1.6 (a) Muscle sympathetic activity during euglycaemia and hypoglycaemia. Reproducedfrom Fagius et al. (1986) courtesy of the American Diabetes Association. (b) Skin sympatheticactivity during euglycaemia and hypoglycaemia. Reproduced from Berne and Fagius (1986), with kindpermission from Springer Science and Business Mediafor 90 minutes after euglycaemia is restored (Figure 1.6a) (Fagius et al., 1986). Duringhypoglycaemia, a sudden increase in skin sympathetic activity is seen, which coincideswith the onset of sweating. This sweating leads to vasodilatation of skin blood vessels,which is also contributed to by a reduction in sympathetic stimulation of the vasoconstrictorcomponents of skin arterio-venous anastomoses (Figure 1.6b) (Berne and Fagius, 1986).These effects (at least initially) increase total skin blood flow and promote heat loss fromthe body.Activation of both muscle and skin sympathetic nerve activity are thought to be centrallymediated. Tissue neuroglycopenia can be produced by 2-deoxy-D-glucose, a glucoseanalogue, without increasing insulin. Infusion of this analogue causes stimulation of muscleand skin sympathetic activity demonstrating that it is the hypoglycaemia per se, and not theinsulin used to induce it, which is responsible for the sympathetic activation (Fagius andBerne, 1989).The activation of the parasympathetic nervous system (vagus nerve) during hypoglycaemiacannot be measured directly. The most useful index of parasympathetic function is themeasurement of plasma pancreatic polypeptide, the peptide hormone secreted by the PP cellsof the pancreas, which is released in response to vagal stimulation.
HORMONAL CHANGES DURING HYPOGLYCAEMIA 13Neuroendocrine Activation (Box 1.3)Insulin-induced hypoglycaemia was used to study pituitary function as early as the 1940s.The development of assays for adrenocorticotrophic hormone (ACTH) and growth hormone(GH) allowed the direct measurement of pituitary function during hypoglycaemia in the1960s, and many of the processes governing these changes were unravelled before eluci-dation of the counterregulatory system. The studies are comparable to those evaluatingcounterregulation, in that potential regulatory factors are blocked to measure the hormonalresponse to hypoglycaemia with and without the regulating factor.Box 1.3 Neuroendocrine activationHypothalamus ↑ Corticotrophic releasing hormone↑ Growth hormone releasing hormoneAnterior Pituitary ↑ Adrenocorticotrophic hormone↑ Beta endorphin↑ Growth hormone↑ Prolactin↔ Thyrotrophin↔ GonadotrophinsPosterior pituitary ↑ Vasopressin↑ OxytocinPancreas ↑ Glucagon↑ Pancreatic polypeptide↑ InsulinAdrenal ↑ Cortisol↑ Epinephrine (adrenaline)↑ AldosteroneOthers ↑ Parathyroid hormone↑ Gastrin↑ Somatostatin (28)Hypothalamus and anterior pituitaryACTH, GH and prolactin concentrations increase during hypoglycaemia, but there is nochange in thyrotrophin or gonadotrophin secretion. The secretion of these pituitary hormonesis controlled by releasing factors which are produced in the median eminence of the hypotha-lamus, secreted into the hypophyseal portal vessels and then pass to the pituitary gland(Figure 1.7). The mechanisms regulating the releasing factors are incompletely understood,but may involve the ventromedial nucleus, one site where brain glucose sensors are situated(Fish et al., 1986).
14 NORMAL GLUCOSE METABOLISM AND RESPONSESFigure 1.7 Anatomy of the hypothalamus and pituitary gland• ACTH: Secretion is governed by release of corticotrophin releasing hormone (CRH) fromthe hypothalamus; alpha adrenoceptors stimulate CRH release, and beta adrenoceptorshave an inhibitory action. A variety of neurotransmitters control the release of CRH intothe portal vessels, including serotonin and acetylcholine which are stimulatory and GABAwhich is inhibitory. The increase in ACTH causes cortisol to be secreted from the corticesof the adrenal glands.• Beta endorphins are derived from the same precursors as ACTH and are co-secreted withit. The role of endorphins in counterregulation is uncertain, but they may influence thesecretion of the other pituitary hormones during hypoglycaemia.• GH: Growth hormone secretion is governed by two hypothalamic hormones: growthhormone releasing hormone (GHRH) which stimulates GH secretion, and somatostatinwhich is inhibitory. GHRH secretion is stimulated by dopamine, GABA, opiates andthrough alpha adrenoceptors, whereas it is inhibited by serotonin and beta adrenoceptors.A study in rats showed that bioassayable GH and GHRH are depleted in the pituitary andhypothalamus respectively after insulin-induced hypoglycaemia (Katz et al., 1967).• Prolactin: The mechanisms underlying its secretion are not established. Prolactin secre-tion is normally under the inhibitory control of dopamine, but evidence also exists forreleasing factors being produced during hypoglycaemia. Prolactin does not contribute tocounterregulation.Posterior pituitaryVasopressin and oxytocin both increase during hypoglycaemia (Fisher et al., 1987). Theirsecretion is under hormonal and neurotransmitter control in a similar way to the hypothalamic
PHYSIOLOGICAL RESPONSES 15hormones. Vasopressin has glycolytic actions and oxytocin increases hepatic glucose outputin dogs, but their contribution to glucose counterregulation is uncertain.Pancreas• Glucagon: The mechanisms of glucagon secretion during hypoglycaemia are still not fullyunderstood. Although activation of the autonomic nervous system stimulates its release,this pathway has been shown to be less important in humans. A reduction in glucoseconcentrations may have a direct effect on the glucagon-secreting pancreatic alpha cells,or the reduced beta cell activity (reduced insulin secretion), which also occurs with lowblood glucose, may release the tonic inhibition of glucagon secretion. However, suchmechanisms would be disturbed in type 1 diabetes, where hypoglycaemia is normallyassociated with high plasma insulin levels and there is no direct effect of beta cell-derivedinsulin on the alpha cells.• Somatostatin: This is thought of as a pancreatic hormone produced from D cells of theislets of Langerhans, but it is also secreted in other parts of the gastrointestinal tract. Thereare a number of structurally different polypeptides derived from prosomatostatin: thesomatostatin-14 peptide is secreted from D cells, and somatostatin-28 from the gastroin-testinal tract. The plasma concentration of somatostatin-28 increases during hypoglycaemia(Francis and Ensinck, 1987). The normal action of somatostatin is to inhibit the secretionboth of insulin and glucagon, but somatostatin-28 inhibits insulin ten times more effec-tively than glucagon, and thus may have a role in counterregulation by suppressing insulinrelease.• Pancreatic polypeptide: This peptide has no known role in counterregulation, but its releaseduring hypoglycaemia is stimulated by cholinergic fibres through muscarinic receptorsand is a useful marker of parasympathetic activity.Adrenal and Renin–Angiotensin systemThe processes governing the increase in cortisol during hypoglycaemia are discussed above.The rise in catecholamines, in particular epinephrine from the adrenal medulla, which occurswhen blood glucose is lowered, is controlled by sympathetic fibres in the splanchnic nerve.The increase in renin, and therefore angiotensin and aldosterone, during hypoglycaemia isstimulated primarily by the intra-renal effects of increased catecholamines, mediated throughbeta adrenoceptors, although the increase in ACTH and hypokalaemia due to hypoglycaemiacontributes (Trovati et al., 1988; Jungman et al., 1989). These changes do not have asignificant role in counterregulation, although angiotensin II has glycolytic actions in vitro.PHYSIOLOGICAL RESPONSESHaemodynamic Changes (Box 1.4)The haemodynamic changes during hypoglycaemia (Hilsted, 1993) are mostly caused bythe activation of the sympathetic nervous system and an increase in circulating epinephrine.
16 NORMAL GLUCOSE METABOLISM AND RESPONSESBox 1.4 Haemodynamic changes↑ Heart rate↑ Systolic blood pressure↑ Cardiac output↓ Peripheral resistance↑ Myocardial contractilityAn increase in heart rate (tachycardia), myocardial contractility and cardiac output occurs,which is mediated through beta1 adrenoceptors, but increasing vagal tone counteracts thiseffect so the increase is transient. Peripheral resistance, estimated from mean arterial pressuredivided by cardiac output, is reduced. A combination of the increase in cardiac output andreduction in peripheral resistance results in an increase in systolic and a decrease in diastolicpressure, i.e. a widening of pulse pressure without a change in mean arterial pressure.Changes in Regional Blood Flow (Box 1.5 and Figure 1.8)• Cerebral blood flow: Early work produced conflicting results, but these studies werein subjects receiving insulin shock therapy, and the varying effects of convulsions andaltered level of consciousness may have influenced the outcome. Subsequent studies haveconsistently shown an increase in cerebral blood flow during hypoglycaemia despite theuse of different methods of measurement (isotopic, single photon emission computedtomography (SPECT) and Doppler ultrasound). In most of the studies blood glucoseconcentration was less than 2 mmol/l before a change was observed. In animals, hypogly-caemia is associated with loss of cerebral autoregulation (the ability of the brain to maintaincerebral blood flow despite variability in cardiac output) through beta adrenoceptor stim-ulation, but the exact mechanisms are unknown (Bryan, 1990; Sieber and Traysman,1992).• Gastrointestinal system: Total splanchnic blood flow (supplying the intestines, liver,spleen and stomach) is increased and splanchnic vascular resistance reduced as assessedby the bromosulphthalein extraction technique (Bearn et al., 1952). Superior mesentericartery blood flow measured using Doppler ultrasound increases during hypoglycaemiadue to beta adrenoceptor stimulation (Braatvedt et al., 1993). Radioisotope scanning hasBox 1.5 Changes in regional blood flow↑ Cerebral flow↑ Total splanchnic flow↓ Splenic flowSkin flow variable (early ↑, late ↓)↑ Muscle flow↓ Renal flow
PHYSIOLOGICAL RESPONSES 17Figure 1.8 Changes in regional blood flow during hypoglycaemiademonstrated a reduction in splenic activity during hypoglycaemia (Fisher et al., 1990),which is thought to be a consequence of alpha adrenoceptor-mediated reduction in bloodflow. These changes would all be expected to increase hepatic blood flow.• Skin: The control of blood flow to the skin is complex and different mechanisms predom-inate in different areas. Studies of the effect of hypoglycaemia on skin blood flow areinconsistent partly because different methods have been used for blood flow measure-ment and induction of hypoglycaemia, as well as differences in the part of the bodystudied. Definitive conclusions are therefore not possible. Studies using the dorsum ofthe foot and the face (cheek and forehead) have consistently shown an initial vasodilata-tion and increase in blood flow followed by later vasoconstriction at a blood glucose of2.5 mmol/l (Maggs et al., 1994). These findings are consistent with the clinical pictureof initial flushing and later pallor, with an early rise in skin blood flow followed by alater fall.• Muscle blood flow: A variety of techniques have been used to study muscle blood flow(including venous occlusion plethysmography, isotopic clearance techniques and the useof thermal conductivity meters). All studies have consistently shown an increase in muscle
18 NORMAL GLUCOSE METABOLISM AND RESPONSESblood flow during hypoglycaemia irrespective of skin blood flow. This change is mediatedby beta2 adrenoceptors (Abramson et al., 1966; Allwood et al., 1959).• Kidney: Inulin and sodium hippurate clearance can be used to estimate glomerular filtrationrate and renal blood flow respectively. Both decrease during hypoglycaemia (Patrick et al.,1989) and catecholamines and renin are implicated in initiating the changes.The changes in blood flow in various organs, like the haemodynamic changes, are mostlymediated by the activation of the sympathetic nervous system or circulating epinephrine. Themajority either protect against hypoglycaemia or increase substrate delivery to vital organs.The increase in cerebral blood flow increases substrate delivery to the brain. Increasingmuscle flow enhances the release and washout of gluconeogenic precursors. The increase insplanchnic blood flow and reduction in splenic blood flow serve to increase hepatic bloodflow to maximise hepatic glucose production. Meanwhile, blood is diverted away fromorgans such as the kidney and spleen, which are not required in the acute response to themetabolic stress.Functional Changes (Box 1.6)• Sweating: Sweating is mediated by sympathetic cholinergic nerves, although other neuro-transmitters such as vasoactive intestinal peptide and bradykinin may also be involved.The activation of the sympathetic innervation of the skin as described above results inthe sudden onset of sweating. Sweating is one of the first physiological responses tooccur during hypoglycaemia and can be demonstrated within ten minutes of achievinga blood glucose of 2.5 mmol/l (Maggs et al., 1994). It coincides with the onset ofother measures of autonomic activation such as an increase in heart rate and tremor(Figure 1.9).• Tremor: Trembling and shaking are characteristic features of hypoglycaemia and resultfrom an increase in physiological tremor. The rise in cardiac output and vasodilata-tion occurring during hypoglycaemia increase the level of physiological tremor and thisis exacerbated by beta adrenoceptor stimulation associated with increased epinephrineconcentrations (Kerr et al., 1990). Since adrenalectomy does not entirely abolish tremor,other components such as the activation of muscle sympathetic activity must beinvolved.Box 1.6 Functional changes↑ Sweating (sudden onset)↑ Tremor↓ Core temperature↓ Intraocular pressure↑ Jejunal activity↑ Gastric emptying
20 NORMAL GLUCOSE METABOLISM AND RESPONSEStemperature (Gale et al., 1983). In rats, mortality was increased in animals whose coretemperature was prevented from falling during hypoglycaemia (Buchanan et al., 1991).In humans there is anecdotal evidence from subjects undergoing insulin shock therapythat those who had a rise in body temperature showed delayed neurological recovery(Ramos et al., 1968). These findings support the hypothesis that the fall in core temper-ature reduces metabolic rate, allowing hypoglycaemia to be better tolerated, and thus thechanges in body temperature are of survival value. The beneficial effects are likely tobe limited, particularly in a cold environment, where the impairment of cerebral func-tion means subjects may not realise they are cold, causing them to be at risk of severehypothermia.• Other functional changes include a reduction in intraocular pressure, greater jejunal butnot gastric motility and inconsistent abnormalities of liver function tests. An increasein gastric emptying occurs during hypoglycaemia (Schvarcz et al., 1995), which maybe protective in that carbohydrate delivery to the intestine is increased, enabling fasterglucose absorption and reversal of hypoglycaemia.CONCLUSIONS• Homeostatic mechanisms exist to maintain glucose concentration within narrow limitsdespite a wide variety of circumstances.• The dependence of the central nervous system on glucose has led to a complex series ofbiochemical, functional and haemodynamic changes aimed at restoring glucose concentra-tions, producing symptoms and protecting the body in general, and central nervous systemin particular, against the effects of a low blood glucose (Figure 1.10).• Many symptoms of hypoglycaemia result from the activation of the autonomic nervoussystem and help to warn the individual that blood glucose is low. This encourages theingestion of carbohydrate, so helping to restore glucose concentrations in addition tocounterregulation.• Faster gastric emptying and the changes in regional blood flow which also occur as aresult of the activation of the autonomic nervous system increase substrate delivery.• The greater cerebral blood flow increases glucose delivery to the brain (although lossof autoregulation is undesirable), and the increased splanchnic flow results in a greaterdelivery of gluconeogenic precursors to the liver.• Activation of the autonomic nervous system also increases sweating, and together with theinhibition of shivering, this predisposes to hypothermia, which may be neuroprotective.ACKNOWLEDGEMENTSWe would like to thank Professor Robert Tattersall for reading the chapter and for his helpfulsuggestions.
REFERENCES 21NORMAL GLUCOSE HOMEOSTASISINSULIN : GLUCAGON RATIO(GH and CORTISOL)COUNTERREGULATIONRESTORE BLOODGLUCOSEADRENALCATECHOLAMINESPITUITARYGLUCAGONSYMPTOMS(Autonomic)SWEATINGHYPOTHERMIAINCREASE SUBSTRATEDELIVERYPROTECTION OFVITAL ORGANSGASTRIC EMPTYINGANDCHANGES IN BLOOD FLOWCEREBRALBLOOD FLOW(eating)HYPOGLYCAEMIADETECTION BY BRAIN GLUCOSE SENSORSExcess InsulinPANCREAS(increased substrateproduction)ACTIVATION OFAUTONOMICNERVOUS SYSTEMBLOOD FLOWSPLANCHNICFigure 1.10 Glucose homeostasis and the correction of hypoglycaemiaREFERENCESAbramson EA, Arky RA, Woeber KA (1966). Effects of propranolol on the hormonal and metabolicresponses to insulin induced hypoglycaemia. Lancet ii: 1386–9.Allwood MJ, Hensel H, Papenberg J (1959). Muscle and skin blood flow in the human forearm duringinsulin hypoglycaemia. Journal of Physiology 147: 269–73.Auer RN, Siesjö BK (1988). Biological differences between ischaemia, hypoglycaemia and epilepsy.Annals of Neurology 24: 699–707.
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24 NORMAL GLUCOSE METABOLISM AND RESPONSESSokaloff (1989). Circulation and energy metabolism of the brain. In: Basic Neurochemistry. Siegel G,Agranoff B, Albers RW and Molinoff P, eds. Raven Press, New York: 565–90.Trovati M, Massucco P, Mularoni E, Cavalot F, Anfossi G, Matiello L, Emanuelli G (1988). Insulin-induced hypoglycaemia increases plasma concentrations of angiotensin II and does not modify atrialnaturetic polypeptide secretion in man. Diabetologia 31: 816–20Wieloch T (1985). Hypoglycemia induced neuronal damage prevented by an N-Methyl D-Aspartateantagonist. Science 230: 681–3.
SYMPTOMS OF HYPOGLYCAEMIA 27appeared before others during hypoglycaemia; that the blood glucose level at which subjectsbecame aware of hypoglycaemia was characteristic for the individual; that there were largeindividual differences in the levels of blood glucose at which awareness of hypoglycaemiacommenced; and that the preceding blood glucose concentration could affect the onset ofsymptoms.Lists of common symptoms of hypoglycaemia have been compiled from more recentresearch. Hepburn (1993) summarised eight population studies of the symptoms ofhypoglycaemia experienced by adults and children with insulin-treated diabetes, and Coxet al. (1993a) also produced a list of symptoms (Table 2.1). It is evident that the three listsof symptoms do not differ greatly, and that Fletcher and Campbell’s early report (1922)had captured many of the symptoms found in subsequent, more structured investigations.However, their report omitted to mention some symptoms such as tiredness, drowsiness anddifficulty concentrating, though it did include others – such as pallor (a sign rather thana symptom), incoordination and feelings of temperature change – that are emphasised byother researchers as regularly perceived symptoms. Table 2.1 establishes a useful group ofsymptoms that are commonly reported in hypoglycaemia.The way we ask people to describe their symptoms of hypoglycaemia can alter what theytell us. The rank order of symptoms alters considerably if patients are asked to indicate therelevance of each symptom rather than merely to identify that the symptom is associatedwith hypoglycaemia (Cox et al., 1993a). With regard to the criterion of relevance, the mostuseful symptoms in detecting hypoglycaemia are as follows:• sweating;• trembling;• difficulty concentrating;• nervousness, tenseness;• light-headedness, dizziness.The initial symptomsAnother important question is: which hypoglycaemic symptoms appear early during anepisode? The symptoms of hypoglycaemia that appear first and offer early warning of theonset of hypoglycaemia (Hepburn, 1993) are as follows:• trembling;• sweating;• tiredness;• difficulty concentrating;• hunger.This knowledge is obviously useful for the prompt detection and treatment of hypoglycaemia.
28 SYMPTOMS OF HYPOGLYCAEMIAThe Validity of Symptom BeliefsThe individuality of hypoglycaemic symptom clustersA great deal of the interest in symptoms of hypoglycaemia has been stimulated by concernsabout patient education. It is helpful to let patients know the range of symptoms found inhypoglycaemia and to inform them of the early warning symptoms reported by other peoplewith diabetes, much as we all tend to know the range of symptoms that are experiencedwith the common cold. Many surveys and laboratory studies have shown that people differconsiderably in the symptoms of hypoglycaemia they experience (Cox et al., 1993a). Inaddition to learning the generally reported symptoms, individuals with diabetes should beencouraged to learn about their own typical symptoms of hypoglycaemia.Correctly interpreting symptoms as representing hypoglycaemiaSymptoms of hypoglycaemia do not appear on top of the bodily equivalent of a blank sheetof paper. Sometimes we experience symptoms when there is nothing wrong with our bodilyfunctions; on the other hand, sometimes we fail to notice any symptoms when the body ismalfunctioning. The alert person with diabetes who is on the lookout for hypoglycaemiamust make two sorts of decisions. First, symptoms of hypoglycaemia must be detected andcorrectly identified. It would be dangerous for a patient to ignore symptoms of hypoglycaemiabecause he or she thought they were related to something else. Second, symptoms that havenothing to do with hypoglycaemia must be excluded. Unwanted hyperglycaemia could occurif patients treated themselves for hypoglycaemia when the symptoms had another cause.These two main types of error are a failure to treat hypoglycaemia when blood glucose islow, and inappropriate treatment when blood glucose is acceptable or high (Cox et al., 1985;1993a) (Figure 2.1).Blood glucose concentration – symptom report correlationsDo patients’ reports of symptoms of hypoglycaemia bear any relation to their concur-rent blood glucose concentrations? After all, the principal aim of educating people to beFigure 2.1 Consequences of correct and incorrect perception of hypoglycaemic symptoms
SYMPTOMS OF HYPOGLYCAEMIA 29aware of symptoms of hypoglycaemia is that they become alert to low and potentiallydangerous levels of blood glucose. To answer the above question some researchers haveemployed a field study approach where people are invited to list any symptoms they areexperiencing, and then measure and record their blood glucose concentration several timesa day for weeks. As a result of these studies it is known that each person has somesymptoms that are most reliably associated with their actual blood glucose concentrations(Pennebaker et al., 1981). Some of the symptoms that people report during hypoglycaemiaare more closely related to their actual blood glucose concentrations than are others, and ifwe can identify each individual’s most informative symptoms, we can instruct people to paymore attention to them.The following symptoms are most consistently associated with actual blood glucoseconcentrations (Pennebaker et al., 1981):• hunger (in 53% of people);• trembling (in 33%);• weakness (in 27%);• light-headedness (in 20%);• pounding heart and fast heart rate (both 17%).The same symptoms are not informative for everyone. There were 27% of people for whomweakness was significantly associated with hypoglycaemia, but there were 7% in whom itwas a good symptom of hyperglycaemia! Most people reported more than three symptomsthat were strongly associated with the measured blood glucose concentration.It is evident that an individual’s symptoms are idiosyncratic. If we can help a patientto identify the symptoms of hypoglycaemia peculiar to him or her, which relate toactual blood glucose concentrations, then, by attending to these symptoms, the personshould be especially accurate in recognising hypoglycaemia. People who have one ormore reliable symptom(s) of hypoglycaemia correctly recognise half of their episodes ofhypoglycaemia (defined as a blood glucose less than 3.95 mmol/l [Cox et al., 1993a]).Those who have four or more reliable symptoms recognise a blood glucose below3.95 mmol/l three-quarters of the time. The field study method has suggested that attentionto the following symptoms was particularly useful in detecting actual low blood glucoseconcentrations:• nervousness/tenseness;• slowed thinking;• trembling;• light-headedness/dizziness;• difficulty concentrating;• pounding heart;• lack of co-ordination.
30 SYMPTOMS OF HYPOGLYCAEMIAClassifying Symptoms of HypoglycaemiaUntil now the symptoms of hypoglycaemia have been treated as a homogeneous whole. Canthese symptoms be divided into different groups?Hypoglycaemia has effects on more than one part of the body, and the symptoms ofhypoglycaemia reflect this. First, the direct effects of a low blood glucose concentrationon the brain – especially the cerebral cortex – cause neuroglycopenic symptoms. Second,autonomic symptoms result from activation of parts of the autonomic nervous system.Finally, there may be some non-specific symptoms that are not directly generated by eitherof these two mechanisms. It is only recently that scientific investigations have taken placeto confirm the idea that these separable groups of hypoglycaemic symptoms exist.As suggested above, there are at least two distinct groups of symptoms during the body’sreaction to hypoglycaemia (Hepburn et al., 1991):• Autonomic, with symptoms such as trembling, anxiety, sweating and warmness.• Neuroglycopenic, with symptoms such as drowsiness, confusion, tiredness, inability toconcentrate and difficulty speaking.This information can assist with patient education by supplying evidence for separablegroups of symptoms, and by indicating which symptoms belong to each group. Someneuroglycopenic symptoms, such as the inability to concentrate, weakness and drowsi-ness, are among the earliest detectable symptoms, but patients tend to rely more on auto-nomic symptoms when detecting the onset of hypoglycaemia. Paying more attention to thepotentially useful, early neuroglycopenic symptoms could help with the early detection ofhypoglycaemia.Similar groups of symptoms of hypoglycaemia have been discovered by asking people torecall the symptoms they typically noticed during hypoglycaemia. However, in addition tothe two groups described above, a general feeling of malaise is added (Deary et al., 1993):• Autonomic: e.g. sweating, palpitations, shaking and hunger.• Neuroglycopenic: e.g. confusion, drowsiness, odd behaviour, speech difficulty andincoordination.• General malaise: e.g. headache and nausea.These 11 symptoms are so reliably reported by people and so clearly separable into thesethree groups, that they are used as the ‘Edinburgh Hypoglycaemia Scale’ (Deary et al.,1993). Table 2.2 shows how different researchers have found similar groups of autonomicand hypoglycaemic symptoms.In addition to the above studies that used patients’ self-reported symptoms, physiologicalstudies have also confirmed that the symptoms of hypoglycaemia can be divided into auto-nomic and neuroglycopenic groups. Symptoms such as sweating, hunger, pounding heart,tingling, nervousness and feeling shaky/tremulous (autonomic symptoms) can be reduced oreven prevented by drugs that block neurotransmission within the autonomic nervous system(Towler et al., 1993), confirming that these symptoms are caused by the autonomic responseto hypoglycaemia. Symptoms such as warmth, weakness, difficulty thinking/confusion,
SYMPTOMS OF HYPOGLYCAEMIA 31Table 2.2 Different authors’ lists of autonomic and neuroglycopenic symptoms of hypoglycaemiaAutonomic NeuroglycopenicDeary et al.(1993)Towler et al.(1993)Weinger et al.(1995)Deary et al.(1993)Towler et al. (1993)Sweating Sweaty Sweating Confusion Difficulty thinking/confusedPalpitation Heart pounding Pounding heart,fast pulseDrowsiness Tired/drowsyShaking Shaky/tremulous Trembling OddbehaviourHunger Hungry SpeechdifficultyDifficulty speakingTingling IncoordinationNervous/anxious Tense WeakBreathing hard Warmfeeling tired/drowsy, feeling faint, difficulty speaking, dizziness and blurred vision (neuro-glycopenic symptoms) are not prevented by drugs that block the autonomic nervous system.Therefore, neuroglycopenic symptoms are not mediated via the autonomic nervous systemand are thought to be caused by the direct effect of glucose deprivation on the brain. Thistype of research has also observed that people tend to rely on autonomic symptoms to detecthypoglycaemia, even when neuroglycopenic symptoms are just as prominent (Towler et al.,1993). Once more, this suggests that more emphasis should be placed on education of thepotential importance of neuroglycopenic symptoms for the early warning of hypoglycaemia.Symptoms might gather into slightly different groupings depending on the situation. Thesymptom groupings in the Edinburgh Hypoglycaemia Scale were developed from diabeticpatients’ retrospective reports. However, when people are asked to rate the same group ofsymptoms during acute, experimentally-induced moderate hypoglycaemia, a slightly differentpattern emerges (McCrimmon et al., 2003). In Table 2.3 there is an autonomic grouping, andthe single neuroglycopenia group has divided into two symptom groups: one with mostlycognitive symptoms and the other with more general symptoms. This division probably arosebecause the subjects in the studies used to form Table 2.3 were engaged in cognitive tasksTable 2.3 Symptom groupings of the Edinburgh Hypoglycaemia Scaleduring experimentally-induced hypoglycaemiaNeuroglycopenic symptomsCognitive dysfunction Neuroglycopenia Autonomic symptomsInability to concentrate Drowsiness SweatingBlurred vision Tiredness TremblingAnxiety Hunger WarmnessConfusion WeaknessDifficulty speakingDouble vision
32 SYMPTOMS OF HYPOGLYCAEMIAduring the period of hypoglycaemia. Therefore, they would be especially aware of cognitiveshortcomings, making this group of symptoms more prominent and coherent.Symptoms in Children and Older PeopleChildren often have difficulty in recognising symptoms of hypoglycaemia, and they showmarked variability in symptoms between episodes of hypoglycaemia (Macfarlane and Smith,1988). Trembling and sweating are often the first symptoms recognised by children. Frominterviews with the parents of children (aged up to 16 years) with type 1 diabetes, andwith some of their children, more is known about the frequency of symptoms of hypo-glycaemia in children (McCrimmon et al., 1995; Ross et al., 1998) (Table 2.4). The mostfrequently reported sign that parents observed was pallor (noted by 88%). The parentsTable 2.4 Symptoms of hypoglycaemia in children (derived from Ross et al., 1998)Frequency of rating (%) Correlation betweenparents’ and children’sintensity ratingsaSymptom Parents’ reports Children’s reportsTearful 73 47 0 40dHeadache 73 65 0 33dIrritable 85 65 0 16Uncoordinated 62 56 0 18Naughty 47 31 0 23bWeak 79 83 0 21bAggressive 75 62 0 26cTrembling 79 88 0 25bSleepiness 63 69 0 27cNightmares 33 19 0 33dSweating 76 73 0 28cSlurred speech 53 45 0 28cBlurred vision 52 55 0 30cTummy pain 67 41 0 36dFeeling sick 63 53 0 32cHungry 74 84 0 19Yawning 48 45 0 20bOdd behaviour 65 50 0 22bWarmness 57 68 0 13Restless 61 57 0 21bDaydreaming 70 48 0 14Argumentative 64 50 0 21bPounding heart 21 44 0 02Confused 75 70 0 41dTingling lips 20 24 −0 01Dizziness 66 87 0 28cTired 83 76 0 26cFeeling awful 92 79 0 20aCorrelations: p of z (corrected for ties) 1.0 represents perfect agreement; 0 represents no agreement.bp < 0 05, cp < 0 01, dp < 0 001.
SYMPTOMS OF HYPOGLYCAEMIA 33frequently reported symptoms of behavioural disturbance such as irritability, argumentative-ness and aggression. This latter group of symptoms is not prominent in adults, althoughthe Edinburgh Hypoglycaemia Scale includes ‘odd behaviour’ as an adult neuroglycopenicsymptom. Others had previously noted the prominence of symptoms such as irritability,aggression and disobedience in the parents’ reports of their children’s symptoms of hypogly-caemia (Macfarlane and Smith, 1988; Macfarlane et al., 1989). Parents tend to under-reportthe subjective symptoms of hypoglycaemia, such as weakness and dizziness, but gener-ally there is good agreement between parents and their children about the most prominentsymptoms of childhood hypoglycaemia (McCrimmon et al., 1995; Ross et al., 1998).Separate groups of autonomic and neuroglycopenic symptoms were not found in childrenwith type 1 diabetes (McCrimmon et al., 1995; Ross et al., 1998). These symptoms arereported together by children and are not distinguished as separate groups, whereas the groupof symptoms related to behavioural disturbance is clearly reported as a distinct group. In arefinement of the earlier study by McCrimmon et al. (1995), Ross et al. (1998) found thatparents could distinguish between autonomic and neuroglycopenic symptoms.People with insulin-treated type 2 diabetes report symptoms during hypoglycaemia thatseparate into autonomic and neuroglycopenic groups (Henderson et al., 2003). Elderlypatients with type 2 diabetes treated with insulin commonly report neurological symptomsof hypoglycaemia which may be misinterpreted as features of cerebrovascular disease, suchas transient ischaemic attacks (Jaap et al., 1998). The age-specific differences in the groupsof hypoglycaemic symptoms, classified using statistical techniques (Principal ComponentAnalysis), are shown in Table 2.5. Health professionals and carers who are involved inthe treatment and education of diabetic patients should be aware of which symptoms arecommon at either end of the age spectrum.From Symptom Perception to ActionPeople with diabetes are better at estimating their blood glucose in natural, everyday situ-ations, as opposed to clinical laboratory settings (Cox et al., 1985). In some ways this issurprising as natural hypoglycaemia often occurs at a time when it is unexpected. In this situ-ation, attention toward symptoms will not be as actively directed toward detection as in thelaboratory setting where it is usually anticipated. Furthermore, hypoglycaemia in everydaylife occurs on the background of other bodily feelings and must be separated from othercauses of the same symptoms. For example, exercise and various acute illnesses can provokesweating in people with diabetes, independently of their association with hypoglycaemia.In a real-life situation a person must detect symptoms of hypoglycaemia and then interpretthem. Failure to detect symptoms can lead to a failure to treat hypoglycaemia, but detectionTable 2.5 Classification of symptoms of hypoglycaemia using Principal Components Analysis inpatients with insulin-treated diabetes depending on age groupChildren (pre pubertal) Adults ElderlyAutonomic/neuroglycopenic Autonomic AutonomicNeuroglycopenic NeuroglycopenicBehavioural Non-specific malaise Neurological
34 SYMPTOMS OF HYPOGLYCAEMIAwithout the correct interpretation of the cause of the symptoms is equally dangerous. Further-more, it is obvious that someone who does interpret symptoms correctly as being causedby hypoglycaemia, but who does not take action to treat the low blood glucose, will be atthe same risk. These and other steps toward the avoidance of severe hypoglycaemia demon-strate the key role of education about symptoms in people with diabetes (Gonder-Fredericket al., 1997). The psycho-educational programmes of Blood Glucose Awareness Training(BGAT; Schachinger et al., 2005) and Hypoglycemia Anticipation, Awareness and Treat-ment Training (HAATT; Cox et al., 2004) have led to better recognition of hypoglycaemicstates and reduced frequency of hypoglycaemia.Symptom generationFigure 2.2 outlines the stages that intervene between low blood glucose occurring in anindividual and the implementation of effective treatment (Gonder-Frederick et al., 1997). Itis interesting to note the importance of behavioural factors in generating states of low bloodglucose. Episodes of low blood glucose are most likely to come about because of changesin routine aspects of diabetes management, such as taking extra insulin, eating less food ortaking more exercise (Clarke et al., 1997). These factors predict more than 85% of episodesof hypoglycaemia in people with diabetes.In the presence of an intact physiological response to low blood glucose, autonomic andneuroglycopenic symptoms, and symptoms of general malaise, are generated (Figure 2.2).The degree of hypoglycaemia, the person’s quality of glycaemic control and any recentepisodes of hypoglycaemia may all affect the magnitude of the body’s physiological response.Recent, preceding hypoglycaemia can reduce the symptomatic and counterregulatoryhormonal responses to subsequent hypoglycaemia, resulting in a diminished awareness ofsymptoms. This effect of ‘antecedent’ hypoglycaemia is described in Chapter 7. Gender doesnot appear to influence the symptomatic response to hypoglycaemia (Geddes et al., 2006).At the second stage in Figure 2.2 comes the actual generation of physical symptoms.Among the variables that can influence this stage is the prior ingestion of caffeine, whichhas been shown to enhance the intensity of the autonomic and neuroglycopenic symptomsof experimentally induced hypoglycaemia (Debrah et al., 1996) (see Chapter 5). Caffeinemay act by increasing the intensity of symptoms of hypoglycaemia to perceptible levels,much as a magnifying glass enables one to read otherwise too-small print.Symptom detectionThe occurrence of physiological changes in the body does not guarantee that a personwill detect symptoms (Gonder-Frederick et al., 1997). If attention is directed to physicalchanges, people are more likely to detect symptoms than if their attention is held elsewhere.Everyone has had the experience of feeling less discomfort, and being less likely to detecta physical symptom, when being distracted by something diverting. The personal relevanceof the symptom may affect detection; for example, a person with heart disease may be verylikely to detect palpitations (Cox et al., 1993a). The activity of the person at the time ofthe physiological change is obviously important. Hypoglycaemic symptoms will be moreobvious to the person engaged in active mental effort (McCrimmon et al., 2003), such assitting an examination, than to the person relaxing and watching television. A doctor engagedin microsurgery may be very sensitive to the onset of tremor. In one laboratory study the
SYMPTOMS OF HYPOGLYCAEMIA 35Figure 2.2 A model for the occurrence and avoidance of severe hypoglycaemia (after Gonder-Frederick et al., 1997). Note on the right-hand side of each stage the factors that affect its occurrencepeople who had higher anxiety levels were better at detecting symptoms of hypoglycaemia(Ryan et al., 2002).The autonomic symptoms of hypoglycaemia are often emphasised in the detection of hypo-glycaemia. However, a strong case can be made for an equal emphasis on neuroglycopenicsymptoms (Gonder-Frederick et al., 1997; McCrimmon et al., 2003) because:• performance on mental tasks deteriorates during hypoglycaemia, and subjective awarenessof this decrement begins at very mild levels of hypoglycaemia• the difference in glycaemic thresholds for the onset of autonomic and neuroglycopenicsymptoms is so small that it is unlikely to be detected when blood glucose declines rapidly
36 SYMPTOMS OF HYPOGLYCAEMIA• neuroglycopenic symptoms are as strongly related to actual blood glucose concentrationsas are autonomic symptoms (Cox et al., 1993a)• people with insulin-treated diabetes cite autonomic and neuroglycopenic symptoms withequal frequency as the primary warning symptoms of hypoglycaemia (Hepburn et al., 1991).Low blood glucose detection – symptom interpretationThe correct detection of a symptom of hypoglycaemia does not always lead to correctinterpretation (Figure 2.2). After correctly detecting relevant symptoms, people fail to detectabout 26% of episodes of low blood glucose (Gonder-Frederick et al., 1997). There areseveral factors that could break a perfect relationship between detection and recognition,and some are discussed below. However, it should be appreciated that symptom detection(internal cues) is not mandatory for the detection of low blood glucose. Self-testing of bloodglucose or the information of family members (external cues) can lead to the successfulrecognition of hypoglycaemia without the patient having detected the episode by symptomaticperception (see Box 2.1).Correct knowledge about symptoms of hypoglycaemia is necessary for the detection oflow blood glucose. The lack of such knowledge among elderly people with diabetes inparticular gives cause for concern (Mutch and Dingwall-Fordyce, 1985). Of 161 diabeticpeople between ages 60 and 87, all of whom were injecting insulin or taking a sulphonylurea,only 22% had ever been told the symptoms of hypoglycaemia and 9% knew no symptomsat all! The percentages of the insulin-treated diabetic patients who knew that the followingsymptoms were associated with hypoglycaemia were as follows:• sweating (82%);• palpitations (62%);• confusion (53%);• hunger (51%);• inability to concentrate (50%);• speech problems (41%);• sleepiness (33%).Box 2.1 Identification of hypoglycaemia• Internal cues – autonomic, neuroglycopenic and non-specific symptoms• External cues – relationship of insulin injection to meals, exercise and experienceof self-management• Blood glucose monitoring• Information from observers (e.g. relatives, friends, colleagues)
ACUTE HYPOGLYCAEMIA AND COGNITIVE FUNCTIONING 37In the midst of this ignorance, much hypoglycaemia may not be treated because of a lackof knowledge of the symptoms of hypoglycaemia which would aid their recognition.Most, if not all, of the symptoms of hypoglycaemia can be explained by other physicalconditions. Therefore, correct symptom detection may be usurped by incorrect attribution ofthe cause. For example, having completed some strenuous activity, an athlete may attributethe symptoms of sweating and palpitations to physical exertion. An obvious problem indetecting a low blood glucose is the fact that the organ responsible for the detectionand interpretation of symptoms – the brain, especially the cerebral cortex – is impaired.Thus, impaired concentration and lowered consciousness levels can beget even more severehypoglycaemia.Symptom scoring systemsThe controversy about the effect of human insulin on symptom awareness (Chapter 7)stimulated the development of scoring systems for hypoglycaemia to allow comparativestudies between insulin species. This produced scoring systems such as the EdinburghHypoglycaemia Scale (Deary et al., 1993), and any such system must be validated forresearch application. It is important to note that the nature and intensity of individualsymptoms are as important as, if not more important than, the number of symptoms gener-ated by hypoglycaemia. The concepts involved are discussed in detail by Hepburn (1993).More information on the symptoms of hypoglycaemia is provided by McAulay et al.(2001b).ACUTE HYPOGLYCAEMIA AND COGNITIVE FUNCTIONINGSymptoms are subjective reports of bodily sensations. With respect to hypoglycaemia someof these reports – especially neuroglycopenic symptoms – pertain to altered cognitive(mental ability) functioning. Do reports of ‘confusion’ and ‘difficulty thinking’ (Table 2.2)concur with objective mental test performance in hypoglycaemia? Before experimentalhypoglycaemia became an accepted investigative tool in diabetes, expert clinical observersnoted impairments of cognitive functions despite clear consciousness during hypoglycaemia(Fletcher and Campbell, 1922; Wilder, 1943). Cognitive functions include the following sortsof mental activity: orientation and attention, perception, memory (verbal and non-verbal),language, construction, reasoning, executive function and motor performance. Early studies(Russell and Rix-Trot, 1975) established that the following abilities become disrupted belowblood glucose levels of about 3.0 mmol/l:• fine motor co-ordination;• mental speed;• concentration;• some memory functions.
38 SYMPTOMS OF HYPOGLYCAEMIAThe hyperinsulinaemic glucose clamp technique allows more controlled experiments ofacute hypo- and hyperglycaemia. However, although this technique is used in most studiesof cognitive function in hypoglycaemia, it does not mimic the physiological or temporalcharacteristics of ‘natural’ or intercurrent episodes of hypoglycaemia experienced by peoplewith type 1 diabetes. From laboratory experiments using the glucose clamp technique it wasfound that blood glucose concentrations between 3.1 and 3.4 mmol/l caused the followingeffects (Holmes, 1987; Deary, 1993):• Slowed reaction times (this experiment involves making a fast response when a lightappears on a computer screen. Hypoglycaemia had more effect on reaction times whenthe reaction involved making a decision).• Slowed mental arithmetic.• Impaired verbal fluency (in this test one has to think of words beginning with a givenletter, probably involving the frontal lobes of the brain).• Impaired performance in parts of the Stroop test (in this test one has to read aloud a seriesof ink colours when words are printed in a different colour from that of the name, e.g. theword RED printed in green ink).Some mental functions were spared during hypoglycaemia, for example:• simple motor (like the speed of tapping) and sensory skills;• the speed of reading words aloud.By 1993 over 16 studies had investigated cognitive functions during acute and mild–moderate hypoglycaemia (Deary, 1993). The levels of blood glucose ranged from 2.0 to3.7 mmol/l. The way that hypoglycaemia was induced varied among studies, as did themethods of blood sampling (e.g. arterialised or venous blood). Moreover, the ability levelsof the people in different studies varied, and there was much heterogeneity in the testbatteries used to assess mental performance. An authoritative statement as to the mentalfunctions disrupted during hypoglycaemia is still not possible. However, in at least one ormore of the studies a number of tests were significantly impaired during hypoglycaemia(Box 2.2).Few areas of mental function are preserved at normal levels during acute hypoglycaemia.There is a general dampening of many abilities that involve conscious mental effort. In theface of so many deleterious effects, what mental functions remain intact during acute hypo-glycaemia? At blood glucose concentrations similar to those indicated above, the followingmental tests are not significantly impaired:• finger tapping;• forward digit span (repeating back a list of numbers in the same order);• simple reaction time;• elementary sensory processing.
ACUTE HYPOGLYCAEMIA AND COGNITIVE FUNCTIONING 39Box 2.2 Cognitive function tests impaired during acute hypoglycaemia• Trail making (involving visual scanning and mental flexibility)• Digit symbol (speed of replacing a list of numbers with abstract codes)• Reaction time (especially involving a decision)• Mental arithmetic• Verbal fluency• Stroop test• Grooved pegboard (a test of fine manual dexterity)• Pursuit rotor (a test of eye–hand co-ordination)• Letter cancellation (striking out occurrences of a given letter in a page of letters)• Delayed verbal memory• Backward digit span (repeating back a list of numbers backwards)• Story recallThus tests which involve speeded responses and which are more cognitively complex andattention-demanding tend to show impairment during hypoglycaemia (Deary, 1993). Hellerand Macdonald (1996) have concluded that:• even quite severe degrees of hypoglycaemia do not impair simple motor functions;• choice reaction time (where a mental decision of some kind is needed before reacting toa stimulus) is affected at higher blood glucose concentrations more than simple reactiontime;• speed of responding is sometimes slowed in a task in which accuracy is preserved;• many aspects of mental performance become impaired when blood glucose falls belowabout 3.0 mmol/l;• there are important individual differences; some people’s mental performance is alreadyimpaired above a blood glucose of 3.0 mmol/l, whereas others continue to function wellat lower levels;• the speed of response of the brain in making decisions slows down during hypoglycaemia(Tallroth et al., 1990; Jones et al., 1990);• it can take as long as 40 to 90 minutes after blood glucose returns to normal for the brainto recover fully (Blackman et al., 1992; Lindgren et al., 1996).
40 SYMPTOMS OF HYPOGLYCAEMIAFigure 2.3 Cognitive effects of hypoglycaemia. After Deary (1998). This Article was published inDiabetes Annual 11, SM Marshall, PD Home and RA Rizza (eds), 97–118, Copyright Elsevier 1998Determining whether mental performance is impaired at all during mild to moderatehypoglycaemia, while a person is still fully conscious, is only the beginning of this lineof investigation. The next question to ask is whether some particular functions are moresusceptible and some less so? Figure 2.3 encapsulates this problem and illustrates three otherimportant questions about the cognitive effects of acute hypoglycaemia:1. What factors affect the degree of cognitive impairment during hypoglycaemia, other thanthe level of blood glucose?2. Do impairments in laboratory cognitive tasks have a bearing on mental performance inreal life?3. Which basic brain functions are disturbed during acute hypoglycaemia?Influences on the Degree of and Threshold for Cognitive DysfunctionDuring Acute HypoglycaemiaAlthough, on average, impairment of mental performance is worse during hypoglycaemia,some people do not change or may even improve (Pramming et al., 1986; Hoffman et al.,
ACUTE HYPOGLYCAEMIA AND COGNITIVE FUNCTIONING 411989). It is not yet certain whether such individual differences in responses are stable(Gonder-Frederick et al., 1994; Driesen et al., 1995). The following factors might increasea person’s degree of cognitive impairment during acute hypoglycaemia:• male sex (Draelos et al., 1995; but this is disputed for people with type 2 diabetes byBremer et al., 2006);• impaired hypoglycaemia awareness (Gold et al., 1995b);• type 1 diabetes (Wirsen et al., 1992);• high IQ (Gold et al., 1995a).Does glycaemic control affect the cognitive impact of hypoglycaemia? People with type1 diabetes on intensified insulin therapy attain glycaemic control that is nearer to normalthan most people treated with conventional insulin treatment. As a result, the frequency ofsevere hypoglycaemia is increased and is associated with a greater risk of impaired hypogly-caemia awareness. Neuroendocrine responses to hypoglycaemia are reduced in magnitudeand begin at lower absolute blood glucose concentrations than in people with less strictglycaemic control. However, the hypoglycaemic threshold for cognitive dysfunction maynot change in a similar fashion. Diabetic patients on intensive insulin therapy reported auto-nomic and neuroglycopenic symptoms at blood glucose concentrations of about 2.4 and2.3 mmol/l respectively, whereas in those with less strict glycaemic control and in non-diabetic individuals, these symptoms commenced at between 2.8 and 3.0 mmol/l. However,in all three groups, the accuracy and speed in a reaction time test deteriorated significantly atblood glucose concentrations between 2.8 and 3.0 mmol/l (Amiel et al., 1991; Maran et al.,1995). Therefore, people with insulin-treated diabetes who have strict glycaemic controlhave the misfortune that the deterioration in their mental performance begins before theonset of warning symptoms of hypoglycaemia. By contrast, neurophysiological responses(P300 event-related potentials), which have been linked to various measures of cognitivefunction, occur at lower blood glucose concentrations, suggesting that cerebral adaptationhas occurred (Ziegler et al., 1992). The effects of quality of glycaemic control, antecedenthypoglycaemia and impaired hypoglycaemia awareness on the mental performance responsesto hypoglycaemia, and the relation of these responses to the perceptions of the symptoms ofhypoglycaemia, are important topics still under study (see Chapters 7 and 8). The interrela-tion of these factors makes the field complex, and progress is further hampered by the lackof consensus agreement on a validated battery of cognitive tests for use in hypoglycaemia.Are the Cognitive Changes During Acute Hypoglycaemia Importantand Valid?Do the impairments of mental test performance actually have implications for real-lifefunctions? In addition, are the mental changes during hypoglycaemia a result of impairmentsin basic brain functions?One common, important and potentially dangerous area of real-life functioning is driving(see Chapter 14), which involves many cognitive abilities including psychomotor controland divided attention. Cox and colleagues (1993b; 2000) employed a sophisticated drivingsimulator and had people ‘drive’ on this during controlled hypoglycaemia using a glucose
42 SYMPTOMS OF HYPOGLYCAEMIAclamp technique. With very mild hypoglycaemia (blood glucose below 3.8 mmol/l) thediabetic drivers committed significant driving errors, and during hypoglycaemia the patientsoften drove very slowly, possibly using a compensatory mechanism to avoid errors. Despitethis, more global errors of driving were committed and about half of the participants,despite demonstrating a seriously impaired ability to drive, said they felt competent to driveirrespective of their low blood glucose! It cannot be stated with certainty that the findingsobtained in a driving simulator will apply to real-life driving. However, studies that examinethe practical cognitive effects of hypoglycaemia are invaluable and more are required.Just as more studies that examine the practical cognitive aspects of hypoglycaemia wouldbe useful, so would more studies of the brain’s processing efficiency. Cognitive tests typicallyinvolve a melange of inseparable mental processes, and yet very specific aspects of the humanbrain’s activities can be measured in the clinical laboratory (Massaro, 1993). Studies of thecognitive effects of hypoglycaemia have thus begun to address the impairments to variouscognitive domains in more detail. Basic, specific aspects of visual and auditory processinghave been examined during acute hypoglycaemia in non-diabetic humans. Standard tests ofvisual acuity – those that are measured by an optometrist – are not affected by hypoglycaemia,but other aspects of vision are affected (McCrimmon et al., 1996). These include:• contrast sensitivity (the ability to discriminate faint patterns);• inspection time (the ability to see what is in a pattern when it is shown for a very briefperiod of time);• visual change detection (the ability to spot a small, quick change in a pattern);• visual movement detection (the ability to spot brief movement in a pattern).This means that the ability to see the environment changes in important ways during hypo-glycaemia. Visual acuity is preserved, as tested by the ability to read black letters on a whitebackground. However, most visual activity is not like that; many of the things we see happenquickly and in relatively poor light. When the level of contrast falls, or discriminationsmust be made under pressure of time, visual processing is impaired during hypoglycaemia.However, at about the same degree of hypoglycaemia, the ability to distinguish one colourfrom another does not appear to be impaired (Hardy et al., 1995). Speed of auditoryprocessing also appears to be impaired by hypoglycaemia, and the ability to discriminatethe loudness of two tones is disrupted (McCrimmon et al., 1997; Strachan et al., 2003).This suggests that the ability to understand language may be compromised during hypogly-caemia. However, despite there being disruption to central nervous system processing duringhypoglycaemia, no disturbance has been detected in peripheral nerve conduction (Strachanet al., 2001).If basic information processing provides a fundamental limitation to how well the brainis operating, then at a higher level of function, attention is important in carrying out anumber of cognitive functions. A detailed study of a number of different aspects of attentionduring hypoglycaemia found that the abilities to attend selectively and to switch attentionas necessary both deteriorated (McAulay et al., 2001a; 2005).In turn, attention is necessary in order to learn and form new memories. There hasnow been detailed study of the different aspects of memory during acute, insulin-inducedhypoglycaemia (Sommerfield et al., 2003a; 2003b; Deary et al., 2003). Most memory
ACUTE HYPOGLYCAEMIA AND EMOTIONS 43systems are disrupted during hypoglycaemia. However, some are especially badly affected:long-term memory, which is the ability to retain new information after many minutes andmuch distraction; working memory, which is the ability to retain and manipulate informationat the same time; and prospective memory, which is the ability to remember to do things (asin a shopping list) (Warren et al., 2007). Indeed, the ability to perform one tricky workingmemory task was obliterated during hypoglycaemia (Deary et al., 2003). That is, no matterhow good the person was at performing the task during euglycaemia, the same task couldnot be done during moderate hypoglycaemia.Further information on hypoglycaemia and cognitive function is available in a review byWarren and Frier (2005).ACUTE HYPOGLYCAEMIA AND EMOTIONSMood change is part of the experience of hypoglycaemia. Moods are emotion-like experi-ences that are quite general rather than applied to specific situations. Psychologists recognisethree basic moods:• energetic arousal (a tendency to feel lively and active rather than tired and sluggish);• tense arousal (a tendency to feel anxious and nervous versus relaxed and calm);• hedonic tone (a tendency to feel happy versus sad).When people are asked to rate their mood states during hypoglycaemia induced in thelaboratory, changes occur in all of these basic mood states. People feel less energetic, moretense and less happy (Gold et al., 1995c; McCrimmon et al., 1999a; Hermanns et al., 2003).During hypoglycaemia the emotional arousal in response to stimuli becomes more intense(Hermanns et al., 2003). In addition, some people become more irritable and have angryfeelings during hypoglycaemia (Merbis et al., 1996; McCrimmon et al., 1999b). The feelingof low energy takes over half an hour to be restored to normal levels, whereas the feelings oftenseness and unhappiness disappear when blood glucose returns to normal. The prolongedfeeling of low energy after hypoglycaemia may affect work performance, so that when hypo-glycaemia has been treated, an immediate return to the normal state should not be expected.In addition to some people experiencing a low, tense, washed-out, angry mood state,hypoglycaemia alters the way some people look at their life problems. When junior doctorswere asked to assess their career prospects during controlled hypoglycaemia, they weremore pessimistic (McCrimmon et al., 1995) and if a general state of pessimism is commonduring hypoglycaemia, it would be a poor state from which to make personal decisions. It ispossible that the change in mood states during hypoglycaemia is one of the causes of adultsadmitting to more ‘odd behaviour’ (Deary et al., 1993). Altered mood may also accountin part for symptoms of behavioural disturbance that are so prominent in the responses tohypoglycaemia of children with diabetes (McCrimmon et al., 1995).In addition to emotional responses as a result of hypoglycaemia, some people haveemotional responses in anticipation of hypoglycaemia. In Edinburgh one young man withinsulin-treated diabetes developed a phobic anxiety state; his phobia related to becomingcomatose as a result of hypoglycaemia (Gold et al., 1997a). Such a case is exceptional,but many people with diabetes are frightened of hypoglycaemia (see Chapter 14). The
44 SYMPTOMS OF HYPOGLYCAEMIAHypoglycaemia Fear Survey (HFS), which comes in two parts, measures this tendency(Cox et al., 1987). The first part asks people several questions concerning how much theyworry about hypoglycaemia (e.g. ‘Do you worry if you have no one around you during a[hypoglycaemic] reaction?’). The second part asks several questions about what people doto avoid hypoglycaemia (e.g. ‘Do you eat large snacks at bedtime?’). People with greaterfear of hypoglycaemia (Polonsky et al., 1992; Hepburn et al., 1994)• have more anxious personalities in general;• are more likely to confuse symptoms of anxiety for those of hypoglycaemia;• report having had more episodes of hypoglycaemia.It is not yet known whether people who experience more hypoglycaemia become worriersabout it, or whether people who are worriers in general just worry more about hypoglycaemiaas well. Perhaps both are true. However, it does seem likely that the experience of more severehypoglycaemia in the past and the development of impaired awareness of hypoglycaemialead to increased worry about subsequent hypoglycaemia (Gold et al., 1997b).CONCLUSIONS• Because people with diabetes are closely involved in their own treatment it is importantthat they and their educators know about the main side-effects and sequelae of the disorderand its treatments.• Accurate knowledge of the symptoms of hypoglycaemia may be used to avoid the dangersof hypoglycaemia.• The progressively more serious impairment in cognitive function that occurs as bloodglucose declines provides knowledge about the brain’s compromised state during hypo-glycaemia: basic functions such as visual processing deteriorate and driving becomesdangerously error-prone. Performance on a host of mental tests becomes worse duringhypoglycaemia.• Some of the neuroglycopenic symptoms of hypoglycaemia are thought to be subjectiveimpressions of impaired cognitive function: these impressions are fully supported by theresults of objective cognitive testing.• Moderate hypoglycaemia may induce a state of anxious tension, unhappiness and lowenergy, and even irritability and anger. Thus hypoglycaemia importantly touches theemotions as well as inducing bodily symptoms and affecting mental performance.REFERENCESAmiel SA, Pottinger RC, Archibald HR, Chusney G, Cunnah DTF, Prior PF, Gale EAM (1991). Effectof antecedent glucose control on cerebral function during hypoglycemia. Diabetes Care 14: 109–18.Blackman JD, Towle VL, Sturis J, Lewis GF, Spire J-P, Polonsky KS (1992). Hypoglycemic thresholdsfor cognitive dysfunction in IDDM. Diabetes 41: 392–9.
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46 SYMPTOMS OF HYPOGLYCAEMIAGold AE, Frier BM, MacLeod KM, Deary IJ (1997b). A structural equation model for predictors ofsevere hypoglycaemia in patients with insulin-dependent diabetes mellitus. Diabetic Medicine 14:309–15.Gonder-Frederick L, Cox D, Driesen NR, Ryan CM, Clarke W (1994). Individual differences inneurobehavioral disruption during mild and moderate hypoglycemia in adults with IDDM. Diabetes43: 1407–12.Gonder-Frederick L, Cox D, Kovatchev B, Schlundt D, Clarke W (1997). A biopsychobehavioralmodel of risk of severe hypoglycemia. Diabetes Care 20: 161–9.Hardy KJ, Scase MO, Foster DH, Scarpello JH (1995). Effect of short term changes in blood glucoseon visual pathway function in insulin dependent diabetes. British Journal of Ophthalmology 79:38–41.Heller SR, Macdonald IA (1996). The measurement of cognitive function during acute hypoglycaemia:experimental limitations and their effects on the study of hypoglycaemia unawareness. DiabeticMedicine 13: 607–15.Henderson JN, Allen KV, Deary IJ, Frier BM (2003). Hypoglycaemia in insulin-treated type 2 diabetes:frequency, symptoms and impaired awareness. Diabetic Medicine 20: 1016–21.Hepburn DA, Deary IJ, Frier BM, Patrick AW, Quinn JD, Fisher M (1991). Symptoms of acute insulin-induced hypoglycemia in humans with and without IDDM. Factor-analysis approach. Diabetes Care14: 949–57.Hepburn DA (1993). Symptoms of hypoglycaemia. In: Hypoglycaemia and Diabetes: Clinical andPhysiological Aspects. Frier BM and Fisher M eds. Edward Arnold, London: 93–103.Hepburn DA, Deary IJ, MacLeod KM, Frier BM (1994). Structural equation modeling of symptoms,awareness and fear of hypoglycemia, and personality in patients with insulin-treated diabetes.Diabetes Care 17: 1273–80.Hermanns N, Kubiak T, Kulzer B, Haak T (2003). Emotional changes during experimentally-inducedhypoglycaemia in type 1 diabetes. Biological Psychology 63: 15–44.Hoffman RG, Speelman DJ, Hinnen DA, Conley KL, Guthrie RA, Knapp RK (1989). Changes incortical functioning with acute hypoglycemia and hyperglycemia in type 1 diabetes. Diabetes Care12: 193–7.Holmes CS (1987). Metabolic control and auditory information processing at altered glucose levels ininsulin dependent diabetes. Brain and Cognition 6: 161–74.Jaap AJ, Jones GC, McCrimmon RJ, Deary IJ, Frier BM (1998). Perceived symptoms of hypoglycaemiain elderly type 2 diabetic patients treated with insulin. Diabetic Medicine 15: 398–401.Jones TW, McCarthy G, Tamborlane WV, Caprio S, Roessler E, Kraemer D et al. (1990). Mildhypoglycemia and impairment of brainstem and cortical evoked potentials in healthy subjects.Diabetes 39: 1550–5.Lindgren M, Eckert B, Stenberg G, Agardh C-D (1996). Restitution of neurophysiological func-tions, performance, and subjective symptoms after moderate insulin-induced hypoglycaemia innon-diabetic men. Diabetic Medicine 13: 218–25.Maran A, Lomas J, Macdonald IA, Amiel SA (1995). Lack of preservation of higher brainfunction during hypoglycaemia in patients with intensively-treated IDDM. Diabetologia 38:1412–18.Massaro DW (1993). Information processing models: microscopes of the mind. Annual Review ofPsychology 44: 383–425.Macfarlane PI, Smith CS (1988). Perceptions of hypoglycaemia in childhood diabetes mellitus: aquestionnaire study. Practical Diabetes 5: 56–8.Macfarlane PI, Walters M, Stutchfield P, Smith CS (1989). A prospective study of symptomatichypoglycaemia in childhood diabetes. Diabetic Medicine 6: 627–30.McAulay V, Deary IJ, Ferguson SC, Frier BM (2001a). Acute hypoglycemia in humanscauses attentional dysfunction while nonverbal intelligence is preserved. Diabetes Care 24:1745–50.
REFERENCES 47McAulay V, Deary IJ, Frier BM (2001b). Symptoms of hypoglycaemia in people with diabetes.Diabetic Medicine 18: 690–705.McAulay V, Deary IJ, Sommerfield AJ, Frier BM (2005). Attentional functioning is impaired duringacute hypoglycaemia in people with type 1 diabetes. Diabetic Medicine 23: 26–31.McCrimmon RJ, Gold AE, Deary IJ, Kelnar CJH, Frier BM (1995). Symptoms of hypoglycemia inchildren with IDDM. Diabetes Care 18: 858–61.McCrimmon RJ, Deary IJ, Huntly BJP, MacLeod KJ, Frier BM (1996). Visual information processingduring controlled hypoglycaemia in humans. Brain 119: 1277–87.McCrimmon RJ, Deary IJ, Frier BM (1997). Auditory information processing during acute insulin-induced hypoglycaemia in non-diabetic human subjects. Neuropsychologia 35: 1547–53.McCrimmon RJ, Deary IJ, Frier BM (1999a). Appraisal of mood and personality during hypoglycaemia.Physiology and Behavior 67: 27–33.McCrimmon RJ, Ewing FME, Frier BM, Deary IJ (1999b). Anger-state during acute insulin-inducedhypoglycaemia. Physiology and Behavior 67: 35–9.McCrimmon RJ, Deary IJ, Gold AE, Hepburn DA, MacLeod KM, Ewing FME, Frier BM (2003).Symptoms reported during experimental hypoglycaemia: effect of method of induction of hypogly-caemia and of diabetes per se. Diabetic Medicine 20: 507–9.Merbis MAE, Snoek FJ, Kanc K, Heine RJ (1996). Hypoglycaemia induces emotional disruption.Patient Education and Counseling 29: 117–22.Mutch WJ, Dingwall-Fordyce I (1985). Is it a hypo? Knowledge of symptoms of hypoglycaemia inelderly diabetic patients. Diabetic Medicine 2: 54–6.Pennebaker JW, Cox DJ, Gonder-Frederick L, Wunsch MG, Evans WS, Pohl S (1981). Physicalsymptoms related to blood glucose in insulin-dependent diabetics. Psychosomatic Medicine 43:489–500.Polonsky WH, Davis CL, Jacobson AM, Anderson BJ (1992). Correlates of hypoglycemic fear in type1 and type 2 diabetes mellitus. Health Psychology 11: 199–202.Pramming S, Thorsteinsson B, Theilgaard A, Pinner EM, Binder C (1986). Cognitive function duringhypoglycaemia in type 1 diabetes mellitus. British Medical Journal 292: 647–50.Ross LA, McCrimmon RJ, Frier BM, Kelnar CJH, Deary IJ (1998). Hypoglycaemic symptoms reportedby children with type 1 diabetes mellitus and by their parents. Diabetic Medicine 15: 836–43.Russell PN, Rix-Trot HM (1975). An exploratory study of some behavioural consequences of insulin-induced hypoglycaemia. New Zealand Medical Journal 81: 337–40.Ryan CM, Dulay D, Suprasongsin C, Becker DJ (2002). Detection of symptoms by adolescents andyoung adults with type 1 diabetes during experimental induction of mild hypoglycemia: role ofhormonal and psychological variables. Diabetes Care 25: 852–8.Schachinger H, Hegar K, Hermanns N, Straumann M, Keller U, Fehm-Wolfsdorf G et al. (2005).Randomized controlled clinical trial of Blood Glucose Awareness Training (BGAT III) in Switzer-land and Germany. Journal of Behavioral Medicine 28: 587–94.Sommerfield AJ, Deary IJ, McAulay V, Frier BM (2003a). Moderate hypoglycemia impairs multiplememory functions in healthy adults. Neuropsychology 17: 125–32.Sommerfield AJ, Deary IJ, McAulay V, Frier BM (2003b). Short-term, delayed, and working memoryare impaired during hypoglycemia in individuals with type 1 diabetes. Diabetes Care 26: 390–6.Strachan MWJ, Deary IJ, Ewing FME, Ferguson SC, Young MJ, Frier BM (2001). Acute hypoglycemiaimpairs the functioning of the central but not peripheral nervous system. Physiology & Behavior72: 83–92.Strachan MWJ, Ewing FME, Frier BM, McCrimmon RJ, Deary IJ (2003). Effects of acute hypo-glycaemia on auditory information processing in adults with type 1 diabetes. Diabetologia 46:97–105.Tallroth G, Lindgren M, Stenberg G, Rosen I, Agardh C-D (1990). Neurophysiological changes duringinsulin-induced hypoglycaemia and in the recovery period following glucose infusion in type 1(insulin-dependent) diabetes mellitus and in normal man. Diabetologia 33: 319–23.
48 SYMPTOMS OF HYPOGLYCAEMIATowler DA, Havlin CE, Craft S, Cryer P (1993). Mechanism of awareness of hypoglycemia: perceptionof neurogenic (predominantly cholinergic) rather than neuroglycopenic symptoms. Diabetes 42:1791–8.Warren RE, Frier BM (2005). Hypoglycaemia and cognitive function. Diabetes, Obesity andMetabolism 7: 493–503.Warren RE, Zammitt NN, Deary IJ, Frier BM (2007). The effects of acute hypoglycaemia on memoryacquisition and recall and prospective memory in type 1 diabetes. Diabetologia 50: 178–85.Weinger K, Jacobson AM, Draelos MT, Finkelstein DM, Simonson DC (1995). Blood glucose esti-mation and symptoms during hyperglycemia and hypoglycemia in patients with insulin-dependentdiabetes mellitus. American Journal of Medicine 98: 22–31.Wilder J (1943). Psychological problems in hypoglycemia. American Journal of Digestive Diseases10: 428–35.Wirsen A, Tallroth G, Lindgren M, Agardh C-D (1992). Neuropsychological performance differsbetween type 1 diabetic and normal men during insulin-induced hypoglycaemia. Diabetic Medicine9: 156–65.Ziegler D, Hubinger A, Muhlen H, Gries FA (1992). Effects of previous glycaemic control on theonset and magnitude of cognitive dysfunction during hypoglycaemia in type 1 (insulin-dependent)diabetic patients. Diabetologia 35: 828–34.
50 FREQUENCY, CAUSES AND RISK FACTORSdecline, a hierarchy of events occur at individual glycaemic thresholds, commencing withcounterregulation (arterialised blood glucose ∼3 8mmol/l), impairment of different cogni-tive functions (∼3 2–2 6mmol/l) and the onset of symptoms and neurophysiological changes(∼3 2–2 4mmol/l). In clinical practice, however, it is usual for venous or capillary bloodglucose levels to be measured, and these are lower than contemporaneous arterialised bloodglucose concentrations (which are usually measured in research studies of hypoglycaemia)(Heller and Macdonald, 1996).In the non-diabetic individual, venous blood glucose concentrations below 3.0 mmol/lmay occur following an overnight fast or during the course of a prolonged oral glucosetolerance test (Service, 1995). Moreover, as is discussed later, the blood glucose thresh-olds for the onset of symptoms and counterregulation in patients with type 1 diabetesmay vary depending on the preceding or prevailing glycaemic control. Thus, patients withpoor glycaemic control may experience symptoms of hypoglycaemia at venous plasmaglucose concentrations substantially higher than 3.0 mmol/l (Boyle et al., 1988). Patientswith preceding strict glycaemic control may not experience the onset of symptoms of hypo-glycaemia until venous plasma glucose concentrations have declined to below 2.0 mmol/l(Boyle et al., 1995). On a pragmatic basis, in routine clinical practice, Diabetes UK hasrecommended that individuals with diabetes should try to ensure that their blood glucoseconcentrations do not fall below 4.0 mmol/l (O’Neill, 1997), but this does not define hypo-glycaemia. The American Diabetes Association has proposed a blood glucose concentrationof 3.9 mmol/l as representing hypoglycaemia (ADA Workgroup on Hypoglycemia, 2005),but this has been challenged as being too high.Clinical Definitions of HypoglycaemiaThe inability to agree on a biochemical definition for hypoglycaemia requires instead theapplication of clinical criteria (Box 3.1). The difficulty here is that because the symptomsof hypoglycaemia are not specific, and vary between individuals (see Chapter 2), the use ofsymptomatology alone may be unreliable and may result in the inclusion of episodes thatare not true hypoglycaemia. In one prospective study, where capillary blood glucose wasmeasured whenever a patient had symptoms suggestive of hypoglycaemia, only 29% of suchepisodes were accompanied by evidence of biochemical hypoglycaemia (i.e., blood glucose<3 0mmol/l) (Pramming et al., 1990). For that reason, hypoglycaemia is usually defined asan episode in which typical symptoms occur and the symptoms are reversed by appropriatetreatment to raise blood glucose. Ideally, corroborative evidence should be provided by thecontemporaneous demonstration of a low capillary or venous blood glucose concentrationbut, as this may be neither available nor possible, it need not be regarded as an absoluterequirement to identify hypoglycaemia.The definition of severe hypoglycaemia used in the Diabetes Control and ComplicationsTrial (DCCT) has gained widespread acceptance and is now regarded as the standarddefinition for clinical research (The Diabetes Control and Complications Trial ResearchGroup, 1997). Severe hypoglycaemia was defined as an episode of hypoglycaemia in whichassistance from a third party was required to effect treatment and recovery. The clearadvantage of this definition is its inherent simplicity, which allows it to be used in a varietyof different clinical and research settings. The disadvantages of the definition are that itdoes not specify a threshold level below which the blood glucose concentration must fall
FREQUENCY OF HYPOGLYCAEMIA 51Box 3.1 Clinical definitions of hypoglycaemia• Asymptomatic hypoglycaemia – low blood glucose identified on routine blood test,with no associated symptoms.• Mild symptomatic hypoglycaemia∗– symptoms suggestive of hypoglycaemia;episode successfully treated by the patient alone.• Severe hypoglycaemia∗– assistance from a third party is required to effect treatment.• Profound hypoglycaemia∗– associated with permanent neurological deficits ordeath.∗Contemporaneous demonstration of a low blood glucose concentration is not mandatory but, particularlyin the case of mild episodes, if it is available it does make the definition more robust.before an episode of hypoglycaemia can be considered to be severe, nor does itspecify any particular method of treating the low blood glucose. There is a substan-tial difference in the degree of neuroglycopenia during an episode of hypoglycaemiathat has resolved following the oral administration of carbohydrate, and one that hasresulted in coma and required the administration of intramuscular glucagon or intravenousglucose.Mild hypoglycaemia is considered to occur when an episode is self-treated by the affectedindividual. Although the recording of episodes of severe hypoglycaemia is generally regardedas being a fairly robust measure, mild hypoglycaemia is a much ‘softer’ end-point. Symptomperception by the patient may be difficult and the glycaemic thresholds at which individualsdevelop symptoms of hypoglycaemia are very variable. In many clinical research studies, itis not uncommon to include a composite definition of mild hypoglycaemia, which includessymptomatic episodes that respond to self-treatment (with or without a confirmatory bloodtest) and asymptomatic episodes below an arbitrary biochemical blood glucose value (e.g.3.5 mmol/l) that have been identified through routine blood glucose monitoring (Andersonet al., 1997). The introduction by some investigators of a further category of ‘moderate’hypoglycaemia is not helpful and confuses the distinction between mild and severeepisodes.FREQUENCY OF HYPOGLYCAEMIAThe true frequency of hypoglycaemia in people with type 1 diabetes is difficult to estimateaccurately and not simply because of differences in the definitions of hypoglycaemia. Mostepisodes occur at home, at work or during leisure activities, without involving medical,nursing or paramedical staff, and the subsequent recall of such episodes by patients isgenerally poor, particularly with regard to mild hypoglycaemia. Prospective studies thereforehave a strong advantage over retrospective studies in their respective abilities to documentthe frequency of hypoglycaemia with accuracy. Another crucially important feature is thenature of the population of people with type 1 diabetes under study – factors such as the
52 FREQUENCY, CAUSES AND RISK FACTORSquality of glycaemic control (The Diabetes Control and Complications Trial Research Group,1997) and the presence of impaired awareness of hypoglycaemia (Gold et al., 1997) havea major influence on the frequency of hypoglycaemia. Participants in clinical interventionalstudies are often not representative of the wider body of people with type 1 diabetes. Forexample, in the DCCT (The Diabetes Control and Complications Trial Research Group,1993), the subjects were young, motivated and received substantial professional support(particularly those in the intensive group). They were pre-selected depending on their historyof hypoglycaemia. Thus, individuals were excluded if, in the previous two years, theyhad experienced more than one episode of severe hypoglycaemia causing neurologicalimpairment, without experiencing warning symptoms, or more than two episodes of seizureor coma, regardless of attributed cause. Such exclusions will have inevitably influenced thebaseline frequency of severe hypoglycaemia in the study groups.Small studies estimating the frequency of hypoglycaemia are likely to be biased becausechance variations in the prevalence of risk factors for hypoglycaemia can magnify (ordiminish) the frequency of hypoglycaemic events to a much greater extent than would beobserved in larger investigations. There is also likely to be a major period effect in studiesof the prevalence of hypoglycaemia. In the post-DCCT era, it might be anticipated thatthe incidence of hypoglycaemia would rise as patients and diabetes healthcare professionalssought to tighten glycaemic control (Johnson et al., 2002). This trend may be counterbalancedby the increased use of home blood glucose monitoring, improved educational programmesand the greater use of insulin analogues and continuous subcutaneous insulin infusion therapy(Chase et al., 2001).Thus, estimates of the frequency of hypoglycaemia must be considered in relation to thedefinitions employed and the characteristics of the patients studied. Comparisons betweenpresent-day and historical studies must be made in the knowledge that treatment targets,methods of monitoring blood glucose and insulin therapy have changed greatly in recentyears.Frequency of Mild, Symptomatic HypoglycaemiaThe features of several studies that have examined the frequency of mild hypoglycaemia,either prospectively or retrospectively, in adults with type 1 diabetes are shown in Table 3.1.Rates of mild hypoglycaemia vary substantially, ranging from 8 to 160 episodes per patientper year. However, it is extremely difficult to make direct comparisons between individualstudies because of differences in methodology and patient characteristics.Retrospective studiesTwo retrospective studies by a Danish group (Pedersen-Bjergaard et al., 2001; Pedersen-Bjergaard et al., 2004) were very similar in their patient characteristics, most of whom wereadministering four or more injections of insulin per day and had moderate glycaemic control.On being asked to recall the number of episodes of mild, symptomatic hypoglycaemiaexperienced in the preceding week, the subjects reported a frequency of two episodes perpatient per week. The strength of these studies lies in the large numbers of patients examinedand the short period of recall. This should have minimised inaccuracy, but may have beenan unrepresentative time frame.
54 FREQUENCY, CAUSES AND RISK FACTORSProspective studiesProspective studies offer the potential to provide more convincing data on frequency of mildhypoglycaemia, but substantial differences in prevalence were again reported. In an earlierstudy of 441 patients with type 1 diabetes, managed principally with a twice daily insulinregimen containing soluble and isophane insulins, the weekly average was 1.8 episodes ofmild symptomatic hypoglycaemia (Pramming et al., 1991). These patients had moderateglycaemic control and the period of assessment was one week. This study may be of lessrelevance today in view of the current use of intensive insulin therapy and insulin analogues,yet it is interesting that the rate of mild hypoglycaemia is unchanged today.A Danish prospective study (Pedersen-Bjergaard et al., 2003a) included patients withsimilar characteristics to those in two retrospective studies by the same group (Pedersen-Bjergaard et al., 2001; Pedersen-Bjergaard et al., 2004). Hypoglycaemia was recordedmonthly with episodes of mild symptomatic hypoglycaemia being reported for the precedingweek. Mild hypoglycaemia occurred on average 1.7 times per patient per week. Subjectswere also asked to perform a monthly five-point blood glucose profile and to record in addi-tion any blood glucose value below 3.0 mmol/l. Measurements demonstrating biochemicalhypoglycaemia represented 3.7% of all blood glucose readings.In a community-based study in Tayside, Scotland, 94 adults with type 1 diabetes wereselected at random from a regional diabetes database and were asked to record episodes ofhypoglycaemia prospectively over one month (Donnelly et al., 2005). Their median age was40 years, median duration of diabetes was 18 years and median HbA1c was 8.3%. Biphasicinsulin was used by 35% of participants and 49% used a combination of intermediate andshort-acting insulins (although the frequency of injections was not reported). A total of325 episodes of mild hypoglycaemia occurred, representing a rate of 41.5 episodes perperson per year, i.e., approximately half the rate reported by Pramming et al., (1991) andPedersen-Bjergaard et al., (2003a). The study has weaknesses; it was relatively small anddata on frequency of blood glucose monitoring were limited. The precise criteria for definingmild hypoglycaemia were not clearly described and, in particular, the role of contempo-raneous monitoring data was not specified. Nevertheless, the subjects were probably veryrepresentative of the population of people with type 1 diabetes in that region.Similar data have been reported from a multicentre study from the United Kingdom (UKHypoglycaemia Study Group, 2007). The primary aim of this study was to compare thefrequencies of hypoglycaemia in individuals with different types and durations of diabetes,receiving different treatment modalities. As part of the study, 50 adults with type 1 diabetesof duration less than five years and 57 adults with type 1 diabetes of greater than 15 yearsduration were recruited. All subjects used two or more injections of insulin per day andtheir glycaemic control was good (mean HbA1c < 8 0%). The participants were followed forbetween 9–12 months (mean 10 months) and were asked to report all episodes of symp-tomatic, self-treated hypoglycaemia and episodes where blood glucose was less 3.0 mmol/l,regardless of symptomatology. Subjects were given forms to record such episodes and wereencouraged to record contemporaneous blood glucose levels. To maximise compliance,subjects were asked to send in completed forms every month to the local research centre,including when no episodes of hypoglycaemia had occurred. If no forms were received,telephone contact was made with the subjects. Using this robust methodology, mean ratesof hypoglycaemia of 35 and 29 episodes per person per year were reported for the shortand long duration groups respectively. The distribution of episodes was much skewed, with
FREQUENCY OF HYPOGLYCAEMIA 55some individuals reporting no events and others in excess of 200 per year; overall, approx-imately 85% of individuals experienced at least one episode of mild hypoglycaemia. Theauthors did not report the relative proportion of symptomatic and asymptomatic episodes, orthe proportion of symptomatic episodes with a corroborative blood test, but these data areextremely informative and indicate that duration of diabetes has little impact on the frequencyof mild hypoglycaemia, an observation that has been made before (Pedersen-Bjergaardet al., 2004).In a 12 month prospective study of 243 insulin-treated adults, Leckie and colleaguesreported that mild, symptomatic hypoglycaemia occurred with a frequency of only eightepisodes per patient per year (Leckie et al., 2005). This is one of the lowest rates to bereported in a large group of people, most of whom had type 1 diabetes. However, severalreasons may account for this result. The subjects had suboptimal glycaemic control, with amean HbA1c of 9.1%. A small number of people with insulin-treated type 2 diabetes wereincluded, who might be expected to have had a lower overall frequency of hypoglycaemia.The prevalence of impaired awareness of hypoglycaemia, a recognised risk factor for hypo-glycaemia (see Chapter 7), was exceptionally low in this cohort at 3%. The proportion ofsubjects using insulin analogues was not reported, but it would certainly have been higherthan in studies from the early 1990s. The main strength of the study, namely a long periodof follow up, may have been an inadvertent weakness by causing ‘patient fatigue’, i.e.,participants may have been less assiduous in recording episodes of mild hypoglycaemia asthe study progressed. Finally, this was primarily a study of the impact of hypoglycaemiaoccurring in the work place. Thus, all of the participants were in full-time employment and sorepresented an atypical group of individuals who may have adopted strategies to reduce thefrequency of hypoglycaemia because of the potentially adverse effects that this could haveon their jobs.Frequency of Asymptomatic, Biochemical HypoglycaemiaAside from the problem of specifying a biochemical threshold for hypoglycaemia, therecan be little doubt that asymptomatic hypoglycaemia is even more common than symp-tomatic, mild hypoglycaemia. However, a major determinant of the frequency of documentedasymptomatic hypoglycaemia is, necessarily, the frequency with which blood glucose ismeasured.Traditionally, two different approaches have been used to investigate this phenomenon:(a) taking multiple sequential blood samples in a controlled, experimental setting, over a pre-specified time period; and (b) inviting patients in the community to perform capillary bloodtests at multiple, pre-set time points. Providing the sampling frame is sufficiently frequent,the advantage of the former strategy is that it will capture all episodes of biochemicalhypoglycaemia, however brief, during the time period under study. The disadvantage isthat it is labour intensive for investigators and so only a small number of subjects can bestudied over a relatively short time period, such as 12 or 24 hours. By contrast, the use ofhome blood glucose monitoring, particularly with meters that store the results electronically,allows larger numbers of subjects to be studied over very prolonged time periods. Typically,subjects are asked to perform periodic seven-point profiles, i.e., blood glucose estimationsbefore each meal, two hours after food and during the night. The obvious disadvantages ofthis mode of investigation are that subjects may forget to perform the relevant monitoring,
FREQUENCY OF HYPOGLYCAEMIA 57Janssen et al., (2000) have studied, prospectively, the frequency of biochemical hypogly-caemia over a six week period in 31 people with type 1 diabetes with a mean HbA1c of7.2% (all had a HbA1c ≤ 8 3%). Subjects were all using a multiple injection regimen withsoluble and isophane insulins and performed one seven-point blood glucose profile and sixfour-point profiles each week. No overnight readings were performed. Patients completeda mean of 82% of the required monitoring schedule and overall experienced a mean of18.7 episodes of hypoglycaemia (i.e., approximately 160 episodes per year). The range waswide, however, at between zero and 41 episodes per individual, over the six weeks ofthe study.The more widespread application of continuous glucose monitoring systems may help toelucidate the frequency of mild hypoglycaemia with greater accuracy. In one study, 65%of people with type 1 diabetes monitored over three days had an episode of asymptomatichypoglycaemia (interstitial glucose < 3 3mmol/l) (Bode et al., 2005). However, much workstill needs to be done to clarify the relationship between interstitial glucose and blood glucoseconcentrations, before this can be regarded as a robust tool for detecting hypoglycaemia (seeChapter 5).Frequency of Severe HypoglycaemiaAs with mild hypoglycaemia, direct comparisons between individual studies on the frequencyof severe hypoglycaemia are not straightforward. However, it is a more robust end-pointthan mild hypoglycaemia and, because episodes typically have a more profound effect onindividuals, retrospective recall is much more reliable. At the conclusion of their prospectivestudy, Pedersen-Bjergaard et al. (2003b), showed that 90% of subjects recalled correctlytheir experience of severe hypoglycaemia over the preceding year (Figure 3.2). Subjectswho had experienced a high incidence of severe hypoglycaemia (prospectively recorded),retrospectively underestimated the overall rate by around 15%.Table 3.2 lists some of the large surveys (each in excess of 100 participants) that haveexamined the frequency of severe hypoglycaemia. The table focuses primarily on studiesexamining unselected groups of individuals with type 1 diabetes, and so excludes interventiontrials (The Diabetes Control and Complications Trial Research Group, 1993; Reichard andPihl, 1994; MacLeod et al., 1995) and studies that examined particular sub-groups of patients,such as people with impaired awareness of hypoglycaemia (Gold et al., 1994; MacLeodet al., 1994; Clarke et al., 1995), differing durations of diabetes (UK Hypoglycaemia StudyGroup, 2007) or subjects who have received intensive therapy or education (Muhlhauseret al., 1985; Pampanelli et al., 1996; Bott et al., 1997). A study that examined a mixedgroup of children, adolescents and adults (Allen et al., 2001) has also been excluded. Thefrequency of severe hypoglycaemia (defined as episodes requiring third party assistance) inthe studies listed in Table 3.2 is remarkably consistent at 1.0 to 1.6 episodes per patientper year.However, it is important to note that the frequency of severe hypoglycaemia in unse-lected populations does not follow a Gaussian distribution (Figure 3.3). The distribution isheavily skewed such that the majority of individuals do not experience any severe hypo-glycaemia in a given year, while a small number of individuals have recurrent episodes. Inthe studies highlighted in Table 3.2, between 30–40% of individuals experienced at leastone episode of severe hypoglycaemia over the period in question. The proportion affected
CAUSES OF HYPOGLYCAEMIA 61CAUSES OF HYPOGLYCAEMIAAlthough advances in insulin therapy have been made over the last 80 years, the adminis-tration of exogenous insulin remains a very crude means of managing type 1 diabetes. Thetime-action profiles of the modern insulin analogues do not mimic the physiological changesin plasma insulin concentrations that occur in non-diabetic individuals (Figure 3.4) and,crucially, concentrations of exogenous insulin cannot respond to changes in blood glucoseconcentration. Therefore, at its most fundamental level, hypoglycaemia in people with type1 diabetes is the result of an imbalance between insulin-mediated glucose efflux from theblood stream and the amount of glucose entering the circulation from ingested carbohydrateand from the liver. Cryer et al. (2003), have grouped the causes of hypoglycaemia intype 1 diabetes into six categories (Box 3.2) depending on their relative effects on insulinFigure 3.4 Mean 24 hour plasma glucose and insulin profiles in 12 healthy non-diabetic individuals.Shaded areas represent 95% confidence intervals. Glucose levels remain within tight limits, while thereis considerable variation in insulin concentrations, particularly around meal times. Reprinted from TheLancet, 358, Owens et al., Insulins today and beyond 739–746 (2001), with permission from ElsevierBox 3.2 Causes of hypoglycaemia in type 1 diabetes1. Inappropriate insulin injection – e.g. excessive dose, inappropriate time, inappro-priate insulin formulation.2. Inadequate exogenous carbohydrate – e.g. missed meal or snack, overnight fast.3. Increased carbohydrate utilisation – e.g. exercise.4. Decreased endogenous glucose production – e.g. excessive alcohol consumption.5. Increased insulin sensitivity – e.g. night time, exercise, weight loss.6. Decreased insulin clearance – e.g. renal failure.Modified from Cryer et al., 2003.
62 FREQUENCY, CAUSES AND RISK FACTORSconcentrations or sensitivity and on glucose entry into the circulation. Although this classi-fication is not perfect, it is a useful starting point for considering the causes of an episodeof hypoglycaemia.Patient ErrorIt is common after an episode of hypoglycaemia for the person with diabetes or, indeeda member of the diabetes team, to try to ascertain why the episode occurred. Althoughthere is always a risk of ‘spurious attribution’, in many instances an obvious cause canbe identified and this is often the result of an error of judgement. Carbohydrate intakemay have been inadequate because a meal was missed or delayed, or simply contained aninsufficient content of carbohydrate. Alternatively, the patient may have injected too muchinsulin relative to the amount of carbohydrate in the meal. It is also not uncommon forinsulin to be administered at an inappropriate time or for the ‘wrong’ insulin to be injectedaccidentally, e.g. a rapid-acting insulin analogue is administered at a time when basal insulinshould have been given. An often unrecognised problem is the inadequate re-suspensionof isophane (or lente) insulins or of fixed mixtures of insulin. If these insulins are notfully resuspended prior to subcutaneous injection, the insulin may be absorbed at variablerates resulting in unpredictable insulin levels and, thus, an increased risk of hypoglycaemia(Owens et al., 2001). Deliberate overdose of insulin is rare, but may result in protractedhypoglycaemia.AlcoholThe relationship of alcohol to hypoglycaemia is considered in detail in Chapter 5. Surveysbased on patient interviews have implicated alcohol in up to one fifth of episodes ofsevere hypoglycaemia requiring hospital admission (Potter et al., 1982; Moses et al., 1985;Feher et al., 1989; Hart and Frier, 1998). In a recent study of 141 people treated forsevere hypoglycaemia in three emergency centres in Copenhagen, alcohol was detectedin the blood of 17% of the subjects (Pedersen-Bjergaard et al., 2005). The median bloodalcohol concentration was 11 mmol/l. Alcohol inhibits gluconeogenesis and so may directlycontribute to the development of hypoglycaemia. In addition, there are some data to suggestthat alcohol attenuates the counterregulatory response to hypoglycaemia (Avogaro et al.,1993; Turner et al., 2001). However, the main impact of alcohol probably centres onits ability to impair awareness of hypoglycaemia and so hinder the ability of individ-uals to take appropriate corrective therapy (Kerr et al., 1990). Thus, an individual underthe influence of alcohol may not recognise that he or she is hypoglycaemic, and evenif the symptoms are recognised, the person may not have the capacity to self-treat. Anepisode of mild hypoglycaemia may therefore be converted rapidly into a severe episode.Moreover, friends, colleagues or bystanders may presume that the neuroglycopenic symp-toms and signs exhibited by the individual are a consequence of alcohol intoxicationand so again appropriate treatment and medical help may not be provided. It is forthese reasons that alcohol is implicated in many instances of profound and protractedinsulin-induced hypoglycaemia associated with permanent neurological damage (Arky et al.,1968).
RISK FACTORS FOR SEVERE HYPOGLYCAEMIA 63ExerciseExercise is recommended for people with type 1 diabetes because of its positive physiologicaland psychological effects. However, exercise can increase the risk of hypoglycaemia bothduring the physical activity itself and in the recovery period (see Chapter 14). The reasonsfor the high incidence of exercise-induced hypoglycaemia in adults with type 1 diabeteshave not been fully elucidated. Moderate exercise in non-diabetic individuals causes a fallin plasma insulin to 40–50% of pre-exercise levels (Galassetti et al., 2003). This normalphysiological decline cannot occur when insulin is being administered exogenously, unlessthe dose is reduced before exercise commences (Sonnenberg et al., 1990). An acute increasein insulin sensitivity following exercise also increases the risk of hypoglycaemia (Sonnenberget al., 1990).The metabolic and counterregulatory hormonal responses to acute hypoglycaemia andexercise are qualitatively very similar. Antecedent exercise blunts the counterregulatoryresponse to subsequent acute hypoglycaemia (Galassetti et al., 2001a; Galassetti et al.,2001b). The inverse situation also applies, i.e., antecedent hypoglycaemia diminishes thecounterregulatory response to subsequent exercise (Galassetti et al., 2003). This means thatat the very time that metabolic substrate requirements are increasing, there is the potentialfor an acute failure of endogenous glucose production. Thus, impaired counterregulatoryresponses may be an important mechanism in promoting exercise-related hypoglycaemia intype 1 diabetes.RISK FACTORS FOR SEVERE HYPOGLYCAEMIAIn a relatively high proportion of cases – in some series as high as 40% (Potter et al., 1982;Feher et al., 1989) – it is not possible to identify the precipitating cause of an episode ofhypoglycaemia. Indeed, this figure may be even higher, because the phenomenon of ‘spuriousattribution’ means that in some instances the perceived precipitant of a given episode mayhave been an innocent bystander. It has, therefore, been increasingly recognised that diabeteshealthcare professionals must look beyond conventional precipitating factors and considerother phenomena which may be associated with an increased risk of hypoglycaemia, namely,the risk factors for hypoglycaemia (Table 3.3). Many of these are discussed in more detailin other chapters.Intensive Insulin TherapyRandomised trials, most notably the DCCT, have provided substantial data on the epidemi-ology of hypoglycaemia in adults with type 1 diabetes and, in particular, on the impact ofintensive insulin therapy.The Diabetes Control and Complications Trial (DCCT)The DDCT was a landmark study and provided diabetes specialists with the long-awaitedproof that strict glycaemic control limited the incidence and severity of microvascularcomplications in people with type 1 diabetes. A total of 1441 patients with type 1 diabetes
RISK FACTORS FOR SEVERE HYPOGLYCAEMIA 65were randomly assigned either to intensive insulin therapy (based on multiple injection insulinregimens or continuous subcutaneous insulin infusion therapy) or to conventional insulintherapy (one or two insulin injections daily) (The Diabetes Control and Complications TrialResearch Group, 1993). In the conventional group, patients did not generally perform homeblood glucose monitoring, clinical reviews were undertaken every three months and patientswere not informed about their HbA1c result, unless it was in excess of 13%. By contrast, inthe intensive therapy group, subjects performed frequent home blood glucose monitoring,had monthly visits with the study team and also had frequent telephone contact to achieve asstrict glycaemic control as possible. Over a mean follow-up of 6.5 years, the average HbA1cconcentration in the intensive group was approximately 7.0% and in the conventional groupapproximately 8.8% (The Diabetes Control and Complications Trial Research Group, 1993).The subjects recruited to this study were not typical of the wider population of people withtype 1 diabetes. The participants had greater motivation and individuals were not permittedto take part if, in the preceding two years, they had experienced more than one episodeof severe neurological impairment without warning symptoms of hypoglycaemia, or morethan two episodes of seizure or coma, regardless of attributed cause. Moreover, during thestudy itself, the occurrence of an episode of severe hypoglycaemia in an individual patientprompted a review of conventional risk factors and, in instances where probable causes wereidentified, corrective actions such as re-educating the patient were undertaken (The DiabetesControl and Complications Trial Research Group, 1997).Despite all these factors, 3788 episodes of severe hypoglycaemia occurred in the 1441patients over the course of the study and, of these, 1027 were associated with coma and/orseizure (The Diabetes Control and Complications Trial Research Group, 1997). The rateof severe hypoglycaemia in the intensively-treated patients was 0.61 per patient per year,while that in the conventionally-treated group was 0.19 per patient per year, i.e., a three-folddifference. Over the mean of 6.5 years of follow-up, 65% of the intensive group experiencedat least one episode of severe hypoglycaemia, compared with 35% of the individuals in theconventional group.The Stockholm Diabetes Intervention Study (SDIS)The SDIS was a much smaller study than the DCCT, but had similar aims and objectives.A group of 102 patients with type 1 diabetes were recruited and 89 remained after 7.5 yearsof follow-up (Reichard and Pihl, 1994). The mean HbA1c was 7.1% in the intensive groupand 8.5% in the conventional group. Severe hypoglycaemia, defined as episodes requiringthird party assistance, occurred in 80% of subjects in the intensive group and 58% of those inthe conventional group over the follow-up period. Overall, the rate of severe hypoglycaemiawas 1.1 per patient per year in the intensive group and 0.4 per patient per year in theintensive group. Other risk factors for severe hypoglycaemia were not reported.The Bucharest-Dusseldorf StudyThe DCCT was a multicentre study; 27 out of the 29 centres reported that intensive therapywas associated with an increased risk of severe hypoglycaemia, but in two centres noincreased risk was observed (The Diabetes Control and Complications Trial Research Group,1997). This led some investigators to claim that with appropriate education and training
66 FREQUENCY, CAUSES AND RISK FACTORSintensive insulin therapy need not necessarily be associated with an increased risk of hypo-glycaemia (Plank et al., 2004). In the Bucharest-Dusseldorf Study, 300 individuals withtype 1 diabetes were randomised to: (a) conventional therapy for one year and then to oneyear of intensive therapy; (b) two years of intensive therapy; or (c) a four-day in-patientgroup teaching programme with conventional insulin therapy for one year (Muhlhauseret al., 1987). Glycated haemoglobin (HbA1), remained unchanged at around 12–13% duringconventional therapy, but fell to ∼9 5% during intensive therapy. In the first year of thestudy, severe hypoglycaemia occurred in 6% of the intensively-treated patients and 12% ofthe conventionally-treated patients, and in year two the proportion of patients experiencingsevere hypoglycaemia in both intensive groups fell to 3–4%.Observational dataThe Dusseldorf team reported observational data on the impact of intensive therapy on thefrequency of severe hypoglycaemia (Bott et al., 1997). A total of 636 people with type1 diabetes who had participated in a structured five-day in-patient treatment and teachingprogramme for intensification of insulin therapy in one of ten different hospitals in Germany,were re-examined at intervals over six years. The mean HbA1c fell from 8.3% to 7.6%.Severe hypoglycaemia, defined as episodes treated with intramuscular glucagon or intra-venous glucose, decreased from 0.28 episodes per patient per year in the year preceding theprogramme to 0.17 episodes per patient per year afterwards (Bott et al., 1997). The varia-tion in incidence of severe hypoglycaemia between different centres ranged from 0.05–0.27episodes per patient per year.Pampanelli and colleagues (1996) from Perugia reported retrospective data on 112 indi-viduals who had been commenced on intensive insulin therapy (preprandial soluble insulinand bedtime isophane insulin) at diagnosis of diabetes and who were attending clinic atleast four times per year. Mean HbA1c was 7.2% and mean duration of diabetes was 7.8years. Frequency of mild hypoglycaemia was estimated by a review of the patients’ bloodglucose monitoring diaries in the nine months prior to study, and the overall rate was 35.6episodes per patient per year. Severe hypoglycaemia, defined as episodes requiring thirdparty assistance, was assessed retrospectively over the duration of diabetes and was recalledby only six patients (representing an overall rate of 0.001 episodes per patient per year).SummaryThus, in the DCCT and the SDIS, intensive insulin therapy was associated with a nearlythree-fold increase in the risk of severe hypoglycaemia. By contrast, in other studies, theincidence of severe hypoglycaemia fell when intensive therapy was coupled with a detailededucation programme. The teams from Dusseldorf and Perugia would argue that the highquality of their education programmes resulted in the low frequencies of observed severehypoglycaemia. Although this may be the case, the importance of patient selection in allof these studies cannot be over-emphasised. In their study of 1076 adults with type 1diabetes from the United Kingdom and Denmark, Pedersen-Bjergaard et al. (2004) examineda subset of 230 individuals whose clinical characteristics were similar to patients enrolledin the DCCT. This sub-group accounted for only 5.4% of all reported episodes of severehypoglycaemia, with an overall rate of 0.35 episodes per patient per year, i.e., approximately
68 FREQUENCY, CAUSES AND RISK FACTORSstatistical adjustment for HbA1c concentration. Indeed, in the intensive group, only about 5%of the variation in frequency of severe hypoglycaemia could be explained by the glycatedhaemoglobin concentration (The Diabetes Control and Complications Trial Research Group,1997).Other studies have reported variable relationships between glycaemic control andfrequency of severe hypoglycaemia. In the study by Bott et al., (1997) a lower mean HbA1cwas associated with severe hypoglycaemia, but there was no linear or quadratic relation-ship between HbA1c and severe hypoglycaemia. In the EURODIAB IDDM ComplicationsStudy, severe hypoglycaemia (defined as episodes requiring third party assistance) occurredin 32% of individuals over 12 months. A clear relationship to glycated haemoglobin wasevident, in that 40% of individuals with an HbA1c < 5 4% were affected compared with24% of individuals with a HbA1c > 7 8% (The EURODIAB IDDM Complications StudyGroup, 1994). In the study of workplace hypoglycaemia, recurrent severe hypoglycaemiawas associated with strict glycaemic control, but no link was found in individuals who hadexperienced only one episode (Leckie et al., 2005). In several other studies, no relation-ship was observed between severe hypoglycaemia and glycated haemoglobin (Muhlhauseret al., 1985; Muhlhauser et al., 1987; MacLeod et al., 1993; Gold et al., 1997; Muhlhauseret al., 1998; ter Braak et al., 2000; Pedersen-Bjergaard et al., 2001; Leese et al., 2003;Pedersen-Bjergaard et al., 2003a; Pedersen-Bjergaard et al., 2004) after adjustment for otherrisk factors.Glycated haemoglobin does not, of course, provide the entire picture about an individual’sglycaemic control and although HbA1c may not predict risk of hypoglycaemia, low meanhome blood glucose concentrations and excessive variability in blood glucose can identifyindividuals more prone to hypoglycaemia (Cox et al., 1994; Janssen et al., 2000).Thus, a straightforward relationship does not exist between severe hypoglycaemia andglycaemic control. For an episode of mild hypoglycaemia to progress to one that causessignificant neuroglycopenia and impairs consciousness, other factors must operate, whichnegate the normal symptomatic and hormonal responses to hypoglycaemia.Acquired Hypoglycaemia SyndromesWithin each treatment group of the DCCT, the number of previous episodes of severehypoglycaemia was the strongest predictor of risk of future episodes (The Diabetes Controland Complications Trial Research Group, 1997). Moreover, approximately 30% of patientsin each group experienced a second episode of severe hypoglycaemia within four monthsfollowing an initial episode. The importance of a previous history of severe hypoglycaemiain predicting future risk has been replicated in several other studies (MacLeod et al., 1993;Bott et al., 1997; Gold et al., 1997; Muhlhauser et al., 1998). Moreover, as demonstrated inTable 3.3, many studies have also linked increased duration of diabetes with an increasedrisk of severe hypoglycaemia.Cryer has suggested that the integrity of the glucose counterregulatory system may be apivotal factor in determining whether the relative or absolute hyperinsulinism that frequentlyoccurs in insulin-treated diabetes ultimately results in the development of hypoglycaemia(Cryer, 1994; Cryer et al., 2003). Three acquired hypoglycaemia syndromes are associatedwith an increased risk of severe hypoglycaemia in people with type 1 diabetes. These areconsidered in greater detail in Chapters 6 and 7.
RISK FACTORS FOR SEVERE HYPOGLYCAEMIA 69Counterregulatory hormonal deficienciesHypoglycaemia-induced secretion of glucagon declines in most patients within five years ofdeveloping type 1 diabetes (Gerich et al., 1973; Bolli et al., 1983). A defective epinephrineresponse to hypoglycaemia may develop some years later (Bolli et al., 1983; Hirsch andShamoon, 1987; Dagogo-Jack et al., 1993). As with the glucagon response, the impairedepinephrine response is hypoglycaemia-specific but, in contrast to glucagon, it exhibits athreshold effect – i.e., an epinephrine response can still be elicited by hypoglycaemia, but onlyat a lower blood glucose concentration (Dagogo-Jack et al., 1993). If hypoglycaemia developsin patients who have this combined counterregulatory hormonal deficiency, glucose recoverymay be severely compromised (see Chapter 6). Subjecting such patients to intensified insulintherapy increased the risk of severe hypoglycaemia by 25 times, compared with subjectswho had an intact epinephrine response (White et al., 1983).Impaired awareness of hypoglycaemiaIn many patients with insulin-treated diabetes, the hypoglycaemia symptom profile alterswith time, resulting in impaired perception of the onset of hypoglycaemia (see Chapter 7).Commonly, autonomic warning symptoms are diminished and neuroglycopenic symptomspredominate. Around 25% of people with type 1 diabetes develop impaired awareness ofhypoglycaemia and the prevalence of this problem increases with the duration of insulintreatment (Hepburn et al., 1990; Gerich et al., 1991; Pramming et al., 1991). Prospectivestudies have demonstrated that the frequency of severe hypoglycaemia is increased up tosix-fold in patients with impaired awareness compared to those with normal hypoglycaemiaawareness (Gold et al., 1994; Clarke et al., 1995).Hypoglycaemia-associated central autonomic failureThe above acquired hypoglycaemia syndromes tend to segregate together clinically. Patientswith glycated haemoglobin concentrations close to the non-diabetic range are at greater riskof developing impaired awareness (Boyle et al., 1995; Kinsley et al., 1995; Pampanelli et al.,1996), while the glycaemic thresholds for the onset of symptoms and responses are alteredin patients with impaired awareness (Grimaldi et al., 1990; Hepburn et al., 1991; Mokanet al., 1994; Bacatselos et al., 1995). Cryer has suggested that these acquired abnormalitiesrepresent a form of central ‘Hypoglycaemia-Associated Autonomic Failure’ (HAAF) in type1 diabetes, speculating that recurrent severe hypoglycaemia is the primary cause (Cryer,1992; Cryer et al., 2003). If hypoglycaemia is the precipitant, then it is possible to see how avicious cycle may become established with the development of the acquired hypoglycaemiasyndromes promoting further episodes of severe hypoglycaemia.SummaryThere is a well-known adage that ‘hypoglycaemia begets hypoglycaemia’. People who haveexperienced one episode of severe hypoglycaemia are much more likely to develop furtherepisodes, and the greatest risk occurs in the weeks and months after the index event. Severehypoglycaemia becomes a more common problem in people with long-standing type 1
70 FREQUENCY, CAUSES AND RISK FACTORSdiabetes (UK Hypoglycaemia Group, 2007). This is the legacy of the burden ofhypoglycaemia that such individuals have experienced over many years with diabetes.The impaired symptomatic and counterregulatory responses to hypoglycaemia dramaticallyincrease the likelihood that an episode of mild hypoglycaemia will progress to a more severeevent.Genetic Predisposition to HypoglycaemiaMost of the precipitants and risk factors for hypoglycaemia have been known about formany years. In 2001, Pedersen-Bjergaard et al. (2001) reported a novel risk factor for severehypoglycaemia in adults with type 1 diabetes and raised the notion that some individualsmay have an inherent genetic susceptibility to hypoglycaemia. The Danish investigatorsnoted the similarity between endurance exercise and hypoglycaemia in that both are statesof limited metabolic fuel availability. Previous studies had linked exercise performance to aparticular polymorphism of the angiotensin-converting enzyme (ACE) gene. Specifically, theinsertion (I) allele, which resulted in low serum ACE activity, was associated with superiorperformance capacity compared with the deletion (D) allele. In an initial retrospective surveyof 207 adults with type 1 diabetes, patients with the DD genotype had a 3.2-fold increasedrisk of severe hypoglycaemia in the preceding two years, compared with individuals withthe II genotype. There was also a significant relationship between serum ACE activity,with a 1.4 increment in risk of severe hypoglycaemia for every 10 U/l rise in serum ACEconcentration (Figure 3.6). The serum ACE activity was directly linked to ACE genotype,and it remained a significant risk factor even after adjustment for conventional risk factors.Moreover, serum ACE activity was a stronger risk factor for severe hypoglycaemia inC-peptide negative individuals with impaired awareness, than in other groups (relative risk1.7 per 10 U/l; Figure 3.7). No significant relationship was observed between serum ACEactivity or genotype and frequency of mild hypoglycaemia.Figure 3.6 Risk of severe hypoglycaemia according to serum ACE activity in 207 patients withtype 1 diabetes, untreated with ACE inhibitors or angiotensin-2 receptor antagonists. Broken linesrepresent 95% confidence intervals. Reprinted from The Lancet, Pedersen-Bjergaard et al. (2001) withpermission from Elsevier
RISK FACTORS FOR SEVERE HYPOGLYCAEMIA 71Figure 3.7 Association between severe hypoglycaemia and serum ACE activity according toC-peptide status and self-estimated awareness of hypoglycaemia. Reprinted from The Lancet, Pedersen-Bjergaard et al. (2001) with permission from ElsevierThese findings were replicated in a prospective study for one year in 107 adults (Pedersen-Bjergaard et al., 2003a). Serum ACE activity in the fourth quartile was associated with a2.7-fold increased risk of severe hypoglycaemia compared to activity in the lowest quartile.Compared to subjects with the II genotype, individuals with the DD genotype had a 1.8-foldincreased risk of severe hypoglycaemia, although this did not reach statistical significance.Higher serum ACE concentrations were also associated with an increased risk of severehypoglycaemia in Swedish children and adolescents with type 1 diabetes (Nordfeldt andSamuelsson, 2003).The Danish group have put forward a number of possible mechanisms to explain theirobservations (Pedersen-Bjergaard et al., 2001; Pedersen-Bjergaard et al., 2003a). They spec-ulate that low levels of serum ACE may be associated with less cognitive deterioration duringacute hypoglycaemia, thereby increasing the likelihood that remedial action to correct hypo-glycaemia is taken. Alternatively, low serum ACE activity might enhance counterregulationor reduce production of toxic substances, e.g. reactive oxygen species, during hypogly-caemia. All these putative mechanisms remain highly speculative, but the authors also raiseone other intriguing possibility: namely that ACE inhibition might reduce the frequency ofhypoglycaemia. This may seem counterintuitive, because previous population-based studiessuggested an association between severe hypoglycaemia and use of ACE inhibitors (Heringset al., 1996; Morris et al., 1997). However, these studies are flawed and a re-examination ofthe role of ACE inhibitors in ameliorating the impact of hypoglycaemia seems warranted.Recent data from one centre in Scotland have not demonstrated such a strong link betweenserum ACE and severe hypoglycaemia in adults with type 1 diabetes (Zammitt et al., 2007),nor has a study of children and adolescents with type 1 diabetes in Australia (Bulsaraet al., 2007). This should, therefore, serve as a reminder that genetic susceptibility to anybiological variable may not be the same in different populations and reinforces the need forthe Danish observations to be examined in other countries and ethnic groups. However, thestudies by Pedersen-Bjergaard and colleagues raise the intriguing prospect that there maybe yet other genetic factors that influence susceptibility to hypoglycaemia. Identification of
72 FREQUENCY, CAUSES AND RISK FACTORSthese may help stratify risk in individuals with type 1 diabetes and may ultimately lead tothe development of novel therapeutic interventions to prevent or ameliorate the impact ofhypoglycaemia.Absent Endogenous Insulin SecretionSeveral studies have demonstrated the importance of endogenous insulin secretion in definingrisk of hypoglycaemia. Individuals who are C-peptide negative, i.e., who have no endogenousinsulin production, have an approximately two- to fourfold increased risk of severe hypogly-caemia compared to people with detectable C-peptide (Bott et al., 1997; The Diabetes Controland Complications Trial Research Group, 1997; Muhlhauser et al., 1998; Pedersen-Bjergaardet al., 2001). These data mirror the clinical experience that severe hypoglycaemia is rare inthe 12 months after the diagnosis of type 1 diabetes (Davis et al., 1997), when significantconcentrations of endogenous insulin can be measured. The presumption is that the abilityof endogenous insulin levels to fall in the face of a declining blood glucose concentrationprovides an additional layer of protection in the defences against hypoglycaemia and thusreduces overall risk.Dose and Type of InsulinFew diabetes specialists who were practising in the mid-1980s will forget the controversythat surrounded the introduction of human insulin. A substantial and vocal minority ofpatients with type 1 diabetes claimed that the change from animal-derived to human insulinwas associated with a loss of warning symptoms of hypoglycaemia and thus an increasedrisk. These claims were subject to considerable scientific scrutiny and ultimately a systematicreview of the evidence found no evidence to support the premise that treatment with human,as opposed to animal, insulin was associated with an increased risk of hypoglycaemia (Aireyet al., 2000).Since that time, several insulin analogues have been developed and their introductioninto clinical practice has been accompanied by the publication of studies that purport todemonstrate that use of the insulin analogues is associated with a lower frequency ofhypoglycaemia, in the face of stable or improved glycaemic control (Anderson et al., 1997;Garg et al., 2004; Hermansen et al., 2004). However, recent systematic reviews suggestthat neither short-acting (Siebenhofer et al., 2004) nor long-acting (Warren et al., 2004)insulin analogues are associated with clinically significant lower rates of hypoglycaemia. Theusual caveats of such clinical trials apply in terms of patient characteristics and recordingof hypoglycaemia. In one observational study from Colorado, the frequency of severehypoglycaemia rose in clinic patients in the immediate aftermath of the DCCT as effortsto intensify insulin therapy were instituted, but from 1996 onwards, the rates of severehypoglycaemia declined and the authors linked this to the introduction of insulin lispro(Chase et al., 2001). This study was subject to the effects of numerous confounders, butfurther data from routine clinical practice are required to help clarify the impact of insulinanalogues on risk of hypoglycaemia. The introduction of inhaled insulin (Exubera) has notbeen associated with a lower risk of hypoglycaemia in either type 1 or type 2 diabetes; whencompared with insulin administered by the subcutaneous route, rates of severe hypoglycaemiawere either equivalent (Hollander et al., 2004) or higher (Skyler et al., 2005).
RISK FACTORS FOR SEVERE HYPOGLYCAEMIA 73Higher doses of insulin have also been associated with an increased risk of hypoglycaemiain some studies (The Diabetes Control and Complications Trial Research Group, 1997;ter Braak et al., 2000), but not in others (Table 3.3). Several possible explanations mayaccount for this relationship – high insulin doses may be a sign of less endogenous insulinproduction, or of efforts to achieve strict glycaemic control. It may also reflect sub-optimalcompliance with insulin therapy and so indicate a pattern of behaviour that predisposes tomarked fluctuations in glucose control.SleepAs has already been discussed in the section on asymptomatic hypoglycaemia, nocturnalhypoglycaemia is very common (Vervoort et al., 1996). In the DCCT, 43% of episodesof severe hypoglycaemia occurred between midnight and 8.00 a.m., and 55% of episodesoccurred when individuals were asleep (The DCCT Research Group, 1991). The potentialfor nocturnal hypoglycaemia engenders significant anxiety among patients, particularly inindividuals who live alone. Patients worry that they will not awaken when hypoglycaemiaoccurs and that they may be left incapacitated or die as a consequence. Many individuals,as a result, maintain higher blood glucose concentrations at bedtime to reduce the risk ofnocturnal hypoglycaemia. Hypoglycaemia appears to be more common at night becausecounterregulatory hormone responses are blunted during sleep in people with type 1 diabetes(Jones et al., 1998; Banarer and Cryer, 2003). Moreover, hypoglycaemia awareness is alsoreduced during sleep (Banarer and Cryer, 2003), and so ultimately sleep impairs both thephysiological and behavioural responses to hypoglycaemia. Unsurprisingly, considerableeffort has been directed at developing strategies to reduce the risk of nocturnal hypoglycaemiaand these are discussed in Chapter 4.Microvascular ComplicationsIn a retrospective study of 44 patients with type 1 diabetes with impaired renal function(serum creatinine ≥ 133umol/l and proteinuria), the incidence of severe hypoglycaemiawas five times higher than in matched subjects with normal renal function (Muhlhauseret al., 1991). In other studies, severe hypoglycaemia was linked with nephropathy (terBraak et al., 2000), peripheral neuropathy and retinopathy (Pedersen-Bjergaard et al., 2004).Although it is generally recognised that insulin requirement declines in advanced renaldisease, with reduced clearance of insulin, this association between hypoglycaemia andnephropathy (and other microvascular complications) could be confounded by many otherfactors, e.g. concomitant drug therapy (ter Braak et al., 2000) and the co-existence ofacquired hypoglycaemia syndromes which, like microvascular complications, are linked withincreasing duration of diabetes.The role of peripheral autonomic neuropathy in increasing the risk of severe hypogly-caemia has been considered in several studies and deserves mention. In the EURODIABIDDM Complications Study, the presence of abnormal cardiovascular reflexes was asso-ciated with a 1.7-fold increased risk of severe hypoglycaemia (Stephenson et al., 1996).Gold et al. (1997) also demonstrated that autonomic neuropathy was associated with asmall increased risk of severe hypoglycaemia in 60 patients with type 1 diabetes, but nosuch relationship was demonstrated in the DCCT (The DCCT Research Group, 1991). The
74 FREQUENCY, CAUSES AND RISK FACTORSmechanism underlying this association remains to be fully elucidated. Peripheral autonomicneuropathy often coexists with impaired hypoglycaemia awareness in patients with type 1diabetes, presumably because both conditions are associated with diabetes of long duration(Hepburn et al., 1990), but impaired awareness can readily occur in the absence of peripheralautonomic neuropathy (Hepburn et al., 1990; Ryder et al., 1990; Bacatselos et al., 1995).It is well established that severe autonomic neuropathy is associated with ‘gastroparesisdiabeticorum’, which can cause marked swings in blood glucose concentration. Althoughsuch severe gastroparesis is now rare, delayed gastric emptying is relatively common (Konget al., 1996) and may explain at least part of the association between hypoglycaemia andautonomic neuropathy.Social and Psychological FactorsPsychological factors clearly play a crucial role in determining an individual’s likelihood ofdeveloping severe hypoglycaemia. Low mood (Gonder-Frederick and Cox, 1997), emotionalcoping (Bott et al., 1997) and socio-economic status (Muhlhauser et al., 1998; Leese et al.,2003) have been linked to risk of severe hypoglycaemia and so too have other morestraightforward behavioural factors such an individual’s propensity to carry a supply ofcarbohydrate for emergency use (Bott et al., 1997) and their determination to achievenormoglycaemia (Muhlhauser et al., 1998).Since the 1980s, Cox and colleagues at the University of Virginia, USA, have carried outseminal investigations to explore the psychological impact of hypoglycaemia on people withtype 1 diabetes. They developed a Fear of Hypoglycaemia scale, which sought to quantifythe anxieties that people with type 1 diabetes have with respect to hypoglycaemia and theextent to which individuals take steps to avoid experiencing such episodes (Cox et al., 1987).Unsurprisingly, there is a close association between fear of hypoglycaemia and perceivedrisk of future severe hypoglycaemia (Gonder-Frederick et al., 1997). In many instances thisis appropriate, in that ‘fear’ ratings are often high in people who have impaired awarenessof hypoglycaemia and/or have experienced multiple episodes in the past (Gold et al., 1996).However, in other people, fear of hypoglycaemia may be high while absolute risk is low –such individuals often display high levels of trait anxiety or have had a traumatic previousexperience of hypoglycaemia. It is often extremely difficult to persuade such individuals tomaintain strict glycaemic control. Conversely, there are people who have a very low fearof hypoglycaemia, despite a propensity to recurrent episodes. Such individuals may fail totake appropriate precautionary measures, thereby putting themselves and others at risk ifhypoglycaemia occurs, for example, when that individual is driving a car.EndocrinopathiesEndocrine disorders, such as Addison’s disease and hypopituitarism, which are associatedwith a deficiency of counterregulatory hormones, can be associated with an increased riskof hypoglycaemia in adults with type 1 diabetes. These are uncommon in everyday diabetespractice, but clinicians should maintain a high index of suspicion particularly in the patientwho simultaneously demonstrates a marked and otherwise unexplained decline in insulinrequirements.
CONCLUSIONS 75Other Risk FactorsThe list of other possible risk factors for hypoglycaemia is a long one. Smoking is a relativelynovel marker of increased risk (Pedersen-Bjergaard et al., 2004), but may be confoundedby other diabetes-related and lifestyle factors, e.g. regular use of alcohol (ter Braak et al.,2000). In the DCCT, men and adolescents were at increased risk (The Diabetes Control andComplications Trial Research Group, 1997), but these associations have not been replicatedwith any consistency in other studies (Table 3.3). Risks associated with pregnancy areaddressed in Chapter 10.Causes and Risk Factors for Hypoglycaemia: Summary andConclusionsMany of the risk factors described above are inter-related and any given individual mayhave more than one, which clearly will increase their overall risk. However, at its mostfundamental level, hypoglycaemia in adults with type 1 diabetes is a consequence of theinability of exogenous insulin levels to fall in response to a declining blood glucose concen-tration. In people who have had type 1 diabetes for several years, the situation is exacer-bated because of a failure of the normal physiological counterregulatory defence mecha-nisms, which in non-diabetic individuals serve to increase exogenous glucose production andgeneratewarningsymptoms.Thiscounterregulatoryfailureworsenswithincreasingdurationofdiabetes, particularly if glycaemic control is strict and the individual has experienced recurrentepisodes of severe hypoglycaemia. Other factors may come in to play, for example particularbehavioural patterns and the time-action profiles of the exogenous insulin. Recent data alsoraise the possibility that there may be inherent genetic susceptibility to hypoglycaemia, butthis needs to be affirmed in wider populations and the underlying mechanisms more clearlydissected. Novel strategies to reduce overall risk of hypoglycaemia are urgently required.CONCLUSIONS• There are no definitive criteria for what constitutes hypoglycaemia, but most specialistsdistinguish mild from severe episodes depending on whether or not the individual is ableto self-treat.• The ‘average’ adult with type 1 diabetes will experience many thousands of episodes of mildhypoglycaemia over a lifetime, with a typical frequency of one to two episodes per week.• Severe hypoglycaemia is less common, and on average occurs once or twice every year,with an annual prevalence of around 30%. However, the distribution is heavily skewed,such that many individuals are unaffected over a calendar year, while a small numberexperience recurrent episodes.• Severe hypoglycaemia requiring treatment with intramuscular glucagon and/or intravenousglucose is even less common, and the majority of all episodes of hypoglycaemia aremanaged in the community by the patient and/or relatives and friends, without recourseto emergency services.
76 FREQUENCY, CAUSES AND RISK FACTORS• Hypoglycaemia occurs when there is an imbalance between insulin-mediated glucosedisposal and glucose influx into the circulation from the liver and exogenous carbo-hydrate. Typical precipitants include patient error in insulin dosage, alcohol andexercise.• Plasma concentrations of exogenous insulin cannot decline in response to falling bloodglucose and the time action profiles of current insulins do not accurately mimic the normalphysiological variation in insulin. In a high proportion of cases, no underlying precipitantof a given episode of hypoglycaemia can be identified.• The DCCT and other intervention studies have provided substantial information of theepidemiology of severe hypoglycaemia, but individuals participating in such studies maynot be representative of the wider population who have type 1 diabetes.• A major determinant of increased risk of severe hypoglycaemia is Hypoglycaemia-Associated Autonomic Failure, which is a consequence of exposure to recurrent episodesof hypoglycaemia. This is a feature of individuals with long-standing diabetes, intensiveinsulin therapy and strict glycaemic control.• Recent data suggest that there may be specific genetic factors that predispose to anincreased risk of hypoglycaemia.REFERENCESAirey CM, Williams DRR, Martin PG, Bennett CMT, Spoor PA (2000). Hypoglycaemia induced byexogenous insulin – ‘human’ and animal insulin compared. Diabetic Medicine 17: 416–32.Allen C, LeClaire T, Palta M, Daniels K, Meredith M, D’Alessio DJ, for the Wisconsin DiabetesRegistry Project (2001). Risk factors for frequent and severe hypoglycemia in type 1 diabetes.Diabetes Care 24: 1878–81.American Diabetes Association Workgroup on Hypoglycemia (2005). Defining and Reporting Hypo-glycemia in Diabetes. Diabetes Care 28: 1245–9.Anderson JH, Brunelle RL, Koivisto VA, Pfutzner A, Trautmann ME, Vignati L, DiMarchi R, TheMulticenter Insulin Lispro Study Group (1997). Reduction of postprandial hyperglycemia andfrequency of hypoglycemia in IDDM patients on insulin-analog treatment. Diabetes 46: 265–70.Arky RA, Veverbrants E, Abramson EA (1968). Irreversible hypoglycemia. A complication of alcoholand insulin. Journal of the American Medical Association 206: 575–8.Avogaro A, Beltramello P, Gnudi L, Maran A, Valerio A, Miola M et al. (1993). Alcohol intakeimpairs glucose counterregulation during acute insulin-induced hypoglycemia in IDDM patients.Evidence for a critical role of free fatty acids. Diabetes 42: 1626–34.Bacatselos SO, Karamitsos DT, Kourtoglou GI, Zambulis CX, Yovos JG, Vyzantiadis AT (1995).Hypoglycaemia unawareness in type 1 diabetic patients under conventional insulin treatment.Diabetes Nutrition and Metabolism 8: 267–75.Banarer S, Cryer PE (2003). Sleep-related hypoglycemia-associated autonomic failure in type 1diabetes. Diabetes 52: 1195–1203.Bode BW, Schwartz S, Stubbs HA, Block JE (2005). Glycemic characteristics in continuously moni-tored patients with type 1 and type 2 diabetes. Normative values. Diabetes Care 28: 2361–6.Bolli G, De Feo P, Compagnucci P, Cartechini MG, Angeletti G, Santeusanio F et al. (1983).Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes 32: 134–41.
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EPIDEMIOLOGY OF NOCTURNAL HYPOGLYCAEMIA? 8521:00765Glucose(mmol/l)4321023:00 01:00 03:00Time (hours)05:00 07:00Figure 4.1 Overnight glucose profiles of one child with type 1 diabetes who was hypoglycaemic onboth study nights. The shaded area represents the range of glucose values from the overnight profilesof the children without diabetesAlthough this is clearly dependent upon the blood glucose level that is designated asrepresenting hypoglycaemia, it is interesting that the studies that reported the lowest ratesof hypoglycaemia had sampled blood glucose less frequently, and it is conceivable thathypoglycaemia at other times of the night was simply not identified. Furthermore, most earlystudies involved patients with poor glycaemic control. It seems likely that with intensiveinsulin therapy now being offered to most patients, rates of nocturnal hypoglycaemia areeven higher. This certainly appears to be true in children. In one alarming study of childrentreated with multiple injection therapy, the rates of nocturnal hypoglycaemia exceeded 50%(Beregszaszi et al., 1997). It is noteworthy that children have been directly observed tosleep through most nocturnal episodes despite having a blood glucose value below 2 mmol/l(Matyka et al., 1999b) (Figure 4.1).The introduction of continuous blood glucose monitoring with glucose being measuredevery few minutes has allowed more frequent recording during sleep. Initial reports usingthese methods have suggested that hypoglycaemic events may be even more commonthan was proposed previously (Table 4.1). However, although continuous blood glucoserecording appears to have revealed a high rate of nocturnal episodes in some studies,it may over-estimate the overall frequency (McGowan et al., 2002). The technologymeasures glucose in the extra cellular space and not in the blood vessels, and the rela-tionship between the glucose concentrations in these sites is not clear (Kulcu et al., 2003).It is also possible that the technology itself produces an inbuilt bias (Wentholt et al.,2005). Nevertheless, not only is nocturnal hypoglycaemia common when measured byconventional blood glucose sampling but it is also often of long duration with someepisodes lasting for more than three hours (Gale and Tattersall, 1979; Matyka et al.,1999b).
86 NOCTURNAL HYPOGLYCAEMIACAUSES OF NOCTURNAL HYPOGLYCAEMIAThe Limitations of Therapeutic Insulin DeliveryThe ability of people with insulin-treated diabetes to maintain strict glucose targets andprevent long-term tissue damage is compromised by the deficiencies of currently availablemethods of insulin delivery. In non-diabetic individuals, endogenous secretion of insulinprecisely meets demand. When food is eaten, insulin secretion increases rapidly to matchnutrient intake, particularly when the ingested food contains carbohydrate. In between meals,basal insulin secretion falls to a low but consistent level to maintain basal metabolism,without the risk of hypoglycaemia, even during prolonged fasting that lasts for hours ordays. In contrast, the limitations of delivering insulin by subcutaneous injection to patientswho can no longer produce endogenous insulin, leads not only to inadequate plasma insulinconcentrations during eating and the immediate postprandial period, but also to inappro-priately raised plasma insulin levels in the post-absorptive phase (Rizza et al., 1980). Thisresults in high postprandial blood glucose concentrations in the hour or so after eating anda tendency to cause hypoglycaemia in the period before the next meal. Individuals areparticularly likely to be affected during the night, when the interval between ingestion offood may be several hours (Box 4.1). As discussed below, developments in insulin deliveryby using insulin analogues or continuous subcutaneous insulin infusion offer some benefitover conventional insulin, although these approaches mitigate rather than cure the problemof nocturnal hypoglycaemia.Impaired Counterregulatory Responses to Hypoglycaemia duringNocturnal HypoglycaemiaVarious mechanisms contribute to the additional risk of developing hypoglycaemia during thenight. Although an earlier study suggested that hormonal responses to hypoglycaemia mightbe increased during nocturnal episodes (Bendtson et al., 1993), recent work has indicatedthat counterregulatory defences are generally impaired. Matyka et al. (1999a) studied 29 pre-pubertal children overnight in their own homes on two separate occasions. They confirmedthat not only was nocturnal hypoglycaemia common, but also that prolonged episodes ofhypoglycaemia were not accompanied by increases in epinephrine (adrenaline) and otherBox 4.1 Factors contributing to the development of nocturnal hypoglycaemia1. Long period between meals (especially in children).2. Inconsistency of conventional subcutaneous basal insulin delivery – nocturnalhyperinsulinaemia.3. Unawareness of early symptoms of hypoglycaemia when asleep.4. Diminished counterregulatory hormone release and symptomatic response in supineposture and effect of sleep per se.
CAUSES OF NOCTURNAL HYPOGLYCAEMIA 87protective endocrine responses. Since protective counterregulatory responses mitigate theseverity of hypoglycaemia by increasing hepatic glucose output and reducing peripheralglucose uptake, as well as enhancing some of the warning autonomic symptoms, defectiveresponses during the night may have a major effect in increasing the risk of nocturnalhypoglycaemia.One important question that emerges from this work is why nocturnal hypoglycaemiashould provoke different physiological responses to those that occur during the day. It nowappears that impaired responses are the result of additional factors at night, in particular asupine posture and also sleep per se.Supine PostureTwo studies have investigated the effect of posture on counterregulatory hormonal defencesto hypoglycaemia. Hirsch et al. (1991) compared the physiological responses to hypogly-caemia induced using a hyperinsulinaemic clamp in young people with type 1 diabetes, whowere either in an upright or a horizontal position. Increments in hypoglycaemic symptomscores were more than 50% lower when patients remained supine compared to the usualincrease that was observed when they were standing erect. These findings have beenconfirmed by other researchers, who also demonstrated that plasma epinephrine levels werethree times lower during hypoglycaemia in the supine position compared to concentrationswhen subjects were standing (Robinson et al., 1994). The precise physiological explanationis not entirely clear but may be related to the recruitment of adrenoreceptors which areprimed by an upright posture. Whatever the cause, these observations suggest that patientsare more vulnerable to progressing to a severe episode of hypoglycaemia when lying hori-zontal in bed, because of a reduction in symptom intensity and in magnitude of hormonalcounterregulation.SleepMost studies have reported suppression of physiological protection by counterregulatorymechanisms during hypoglycaemia. Jones et al. (1998) lowered blood glucose to 2.8 mmol/lboth during the daytime and at night, and demonstrated diminished epinephrine responsesin diabetic and non-diabetic adolescents while they were asleep when compared to thebrisk responses while they were awake, whether during daytime hours or during the night(Figure 4.2). Banerer and Cryer (2003) confirmed these observations in patients with type 1diabetes but, interestingly, in non-diabetic subjects no difference in epinephrine responsewas observed between these states. Diminished counterregulatory responses, includingepinephrine, have also been demonstrated during spontaneous nocturnal hypoglycaemicepisodes in children with diabetes (Matyka et al., 1999a). Therefore, sleep appears to beassociated with diminished catecholamine and symptomatic responses to hypoglycaemiawith a reduction in wakening during a hypoglycaemic episode. The diminished responsemay occur because the glycaemic thresholds for activation of these responses have beenreset to a lower glucose level (Gais et al., 2003), so that more profound hypoglycaemia isnecessary to provoke a similar response to that observed in subjects when they are awake.As the investigators involved in these studies have pointed out, this increases the risk of a
CONSEQUENCES OF NOCTURNAL HYPOGLYCAEMIA 89reported by patients because they remain asleep, but may contribute to the development ofimpaired awareness of hypoglycaemia.The ‘Dead in Bed’ SyndromeThe possible contribution of hypoglycaemia to cardiac arrhythmias and sudden death isdiscussed in detail in Chapter 12. However, since it has been proposed that nocturnalhypoglycaemia may be a specific precipitant, it merits a brief mention here. A detailed surveyof unexpected deaths in young people with type 1 diabetes in the early 1990s highlighted arare but distinct mode of death in which young people were found lying in an undisturbed bed.Autopsy failed to reveal a structural cause but circumstantial evidence implicated nocturnalhypoglycaemia as a precipitant. Not all affected individuals had strict glycaemic control, butmany were known to have been susceptible to developing nocturnal hypoglycaemia. Thistype of sudden and unexpected death has since been confirmed in epidemiological surveysin other countries, possibly accounting for between 5–10% of all deaths under the age of40 in people with diabetes. Hypoglycaemia causes an increase in the QT interval and onepossible explanation is that an episode of nocturnal hypoglycaemia triggers a ventriculararrhythmia in a susceptible individual. However, further work is required to establish thisplausible hypothesis as the cause of these deaths.Neurological Consequences of Nocturnal Hypoglycaemia on CerebralFunctionThe possibility that recurrent exposure to hypoglycaemia, particularly occurring during sleep,might insidiously damage cerebral function and cause permanent cognitive impairment wasraised by the finding that children who had developed type 1 diabetes before the age offive years, exhibited cognitive impairment when compared with non-diabetic controls (Ryanet al., 1985). This observation was replicated in different studies using a range of cognitivetests (Bjorgaas et al., 1997; Rovet and Ehrlich, 1999).However, the relationship to hypoglycaemia, particularly during the night, was unclear(Golden et al., 1989); hypoglycaemia-induced convulsions have also been implicated, and itis possible that other factors associated with early-onset diabetes may contribute to cognitiveimpairment.Several studies have explored the extent to which nocturnal episodes may affect perfor-mance on the following day. Bendtson et al. (1992) found no difference in cognitive perfor-mance among adults with type 1 diabetes when tested on the morning after an episode ofnocturnal hypoglycaemia in comparison with a night with no hypoglycaemia. Similar findingshave been reported after the induction of experimental hypoglycaemia during the night (Kinget al., 1998) although the subjects were more fatigued on the following morning. It seemsthat even children are relatively unaffected by a single episode of nocturnal hypoglycaemia.Matyka et al. (1999b) tested pre-pubertal children after episodes of prolonged, spontaneouslyoccurring, hypoglycaemia that occurred during sleep, many of which lasted several hours,and found no deleterious effect on cognitive function on the following morning, althoughmood was adversely affected.In summary, although it seems plausible that recurrent nocturnal hypoglycaemia mightcontribute to cognitive decline, on the available evidence the verdict remains unproven.
90 NOCTURNAL HYPOGLYCAEMIACAN NOCTURNAL HYPOGLYCAEMIA BE PREDICTED?The ability to predict whether a nocturnal hypoglycaemic episode is likely, by measuringglucose concentrations at bedtime, has generally been tested in studies using intermittentblood glucose sampling to detect hypoglycaemia. It is likely that such a design will failto identify all episodes. The results of two early studies that observed patients who werereceiving one or two daily injections of insulin, suggested that a bedtime glucose concentra-tion of 6.0 mmol/l or less indicated an 80% chance of a period of biochemical hypoglycaemiaduring the night (Pramming et al., 1985; Whincup and Milner, 1987). Furthermore, theseearly studies were generally undertaken among patients who were taking two injectionsof conventional insulins each day. Studies of children have suggested that blood glucosemeasurements at bedtime are less predictive of hypoglycaemia in the first half of thenight, although a value of < 7 5mmol/l does indicate an increased risk (Matyka et al.,1999b). That study and others have also shown that a low fasting blood glucose is astrong indicator that hypoglycaemia has occurred in the latter half of the night (Matyka,2002).Since severe nocturnal hypoglycaemia is relatively rare, it is much more difficult toestablish to what extent bedtime blood glucose values are predictive. A previous historyof severe hypoglycaemia, impaired awareness of hypoglycaemia or strict control with lowHbA1c values, will confer a greater chance of a severe episode but are a poor guide to therisk of developing a severe nocturnal episode on any particular night.THE SOMOGYI PHENOMENON: THE CONCEPT OF REBOUNDHYPERGLYCAEMIAIn the late 1930s, a Hungarian biochemist, Michael Somogyi, working in St Louis, USA,suggested that nocturnal hypoglycaemia might provoke rebound hyperglycaemia on thefollowing morning, and he supported his hypothesis with a demonstration that reducingevening doses of insulin led to a reduction in fasting urinary glycosuria (Somogyi, 1959). Heproposed that nocturnal hypoglycaemia provokes a counterregulatory response with rises inplasma epinephrine, cortisol and growth hormone resulting in the release of glucose from theliver and inhibition of the effects of insulin over the next few hours. The logical conclusionfrom his hypothesis was that this ‘rebound’ elevated fasting blood glucose in the morningshould be treated, not by an increase in the evening dose of insulin, but paradoxically by areduction. The idea of ‘rebound hyperglycaemia’ following nocturnal hypoglycaemia, (alsoknown as the Somogyi phenomenon) as an explanation for a high fasting blood glucosein insulin-treated patients, has proved to be very attractive to many diabetes healthcareprofessionals who firmly believe in its existence. The consequences are important as patientsare often advised to reduce their evening insulin dose, particularly if they complain ofnocturnal hypoglycaemia. However, its clinical relevance was challenged over 20 years agoand repeated studies have established that fasting hyperglycaemia is largely a result of fallingplasma insulin concentrations during the night, as the subcutaneous depot of insulin that wasinjected the day before is dissipated.Gale et al. (1980) demonstrated that periods of hypoglycaemia during the night wereoften prolonged and were not accompanied by a large rise in counterregulatory hormones.
THE SOMOGYI PHENOMENON 911.00.80.6Probabilityofhypoglycaemicepisodesinthenight0.40.22 3 4 5 6 7 8 9 10 11Morning blood glucose (mmol/I)12 13 14 15 16 17 18 19 20 21Figure 4.3 Risk of nocturnal hypoglycaemia according to fasting morning blood glucose (95% Cl) in594 nights. Black bars = hypoglycaemic nights; shaded bars = possibly hypoglycaemic nights. Repro-duced from Hoi-Hansen et al. (2005). With kind permission from Springer Science and Business MediaAlthough fasting glucose concentrations were frequently high in the patients they studied,this was related directly to a waning of circulating plasma insulin concentrations. Someinvestigators have demonstrated that when hypoglycaemia is experimentally-induced duringthe night, this can raise blood glucose on the following morning, even if circulating plasmainsulin concentrations are maintained (Perriello et al., 1988). However, the additional increasein the fasting blood glucose concentration is modest (around 2.0 mmol/l) and its clinicalrelevance is questionable. Other researchers have found no effect on daytime concentrationsof blood glucose after lowering blood glucose to hypoglycaemic levels during the night(Hirsch et al., 1990). Careful analysis of data collected both by self-monitoring of bloodglucose (Havlin and Cryer, 1987) and by continuous glucose monitoring (Hoi-Hansen et al.,2005) (Figure 4.3) during everyday activities, has also shown that nocturnal hypoglycaemiadoes not provoke rebound fasting hyperglycaemia.Many insulin-treated diabetic patients experience high fasting blood glucose levels butthis common clinical problem is essentially a consequence of inadequate basal insulinreplacement overnight. The important mechanisms that contribute to fasting hyperglycaemiaappear to be a combination of waning plasma insulin levels and glucose release fromthe liver secondary to nocturnal spikes of growth hormone secretion (Campbell et al.,1985), a physiological process termed the ‘dawn phenomenon’. High blood glucose levelsfollowing symptomatic nocturnal hypoglycaemia may also result from excessive intakeof oral carbohydrate, ingested as treatment of the hypoglycaemia, rather than a powerfulcounterregulatory response, which is usually suppressed at night. The clinical message istherefore clear: fasting hyperglycaemia indicates a need for adjusting basal insulin in termsof type or timing rather than reducing the dose. Some useful clinical steps to be undertakenin patients presenting with this problem are listed in Box 4.2.
92 NOCTURNAL HYPOGLYCAEMIABox 4.2 Clinical approach to high fasting blood glucose complicated by nocturnalhypoglycaemia1. Measure blood glucose at 2–3 a.m. over a few days.2. If nocturnal hypoglycaemia is present, ensure that basal insulin is taken at bedtime(i.e., split pre-mixed evening insulin).3. Progressively increase bedtime long-acting insulin in doses of 2–4 units whilechecking with 3 a.m. blood glucose measurements that this is not precipitatingnocturnal hypoglycaemia4. Use a long-acting insulin analogue, either glargine or detemir.5. Teach patients to take an appropriate (but not excessive) quantity of a high energyglucose drink, orange juice or glucose as sweets or tablets to treat nocturnal hypo-glycaemic episodes.6. When available, consider obtaining a continuous glucose monitoring profile.CLINICAL SOLUTIONS (BOX 4.3)Dietary MeasuresA time honoured approach to reducing the frequency of nocturnal hypoglycaemia has beento counteract the effect of insulin by ensuring that patients eat a bedtime snack. This seemedparticularly important for children who go to bed early and sleep for many hours betweentheir evening insulin dose and breakfast on the following day. It clearly makes sense for allindividuals taking insulin to measure their blood glucose before bed and to take additionalfood if their blood glucose is low. However, the extent to which protective eating can preventnocturnal hypoglycaemia in patients taking intermittent injections of insulin is limited.Box 4.3 Potential remedies for problematical nocturnal hypoglycaemia1. Long and rapid-acting insulin analogues.2. -agonists (terbutaline or salbutamol).3. Appropriate snacks:– uncooked cornstarch– high protein foods.4. CSII.
CLINICAL SOLUTIONS 93The effectiveness of different approaches has generally been assessed by measuring theeffectiveness of different snacks in preventing biochemical or symptomatic episodes ofhypoglycaemia. Before the advent of continuous blood glucose monitoring, such studiesdemanded regular blood sampling for measurement of glucose and since this generallyrequired admission to hospital for study, these investigations were not exactly examininga typical clinical situation. Furthermore, the number of subjects studied has generally beenrelatively small, and although sufficient to measure changes in blood glucose concentrationor frequency of biochemical hypoglycaemia, the studies have been inadequately poweredto determine effects on the frequency of severe episodes. Some studies have examinedthe potential of carbohydrate foods that are absorbed slowly and thus able to counter thehypoglycaemic effect of insulin over longer periods. Uncooked cornstarch, which has a verylow glycaemic index, has been studied intensively, particularly because it is used successfullyto prevent severe hypoglycaemia in glycogen storage diseases (Goldberg and Slonim, 1993).In one study, when young people were given uncooked cornstarch incorporated into a normalbedtime snack, the incidence of symptomatic and biochemical nocturnal hypoglycaemiawas three-fold lower (Kaufman and Devgan, 1996). A blinded randomised trial reported asimilarly lower frequency of nocturnal episodes (Kaufman et al., 1997). Other work hasexamined the effect of snacks rich in protein or fat.Different types of snack were compared against placebo in a trial using a crossoverdesign in 15 adults with type 1 diabetes (Kalergis et al., 2003). When patients retired tobed with blood glucose greater than 10.0 mmol/l, nocturnal episodes were not observed.At a pre-bedtime glucose below 7.0 mmol/l, a high protein snack prevented any episodeof nocturnal hypoglycaemia by contrast with either a standard snack or one containingcornstarch (Figure 4.4). Thus the clinical data measuring the effectiveness of cornstarch are100%80%60%40%%Nights20%0%Pl S CS<7 mmol/L 7–10 mmol/LBedtime blood glucose category>10 mmol/LProt Pl S CS Prot Pl S CS ProtFigure 4.4 Effect of snacks and bedtime blood glucose concentration on frequency of nocturnalhypoglycaemia. Open box = neither nocturnal hypoglycaemia nor morning hypoglycaemia; solidblack box = hypoglycaemia; striped box = morning hypoglycaemia only. Snack type: Pl = placebo;S = standard diet; CS = cornstarch; prot = protein
94 NOCTURNAL HYPOGLYCAEMIAconflicting. Since uncooked cornstarch is not easy to prepare in a digestible form, it is notsurprising that it is not used widely to prevent nocturnal hypoglycaemia.An alternative approach to dietary supplements is to reduce the rate of absorption ofcarbohydrates using a disaccharidase inhibitor such as acarbose. Three studies of theseagents have examined their effects in patients with type 1 diabetes. McCulloch et al. (1983)studied the effect of acarbose on the risk of overnight hypoglycaemia, and found that therisk of symptomatic nocturnal hypoglycaemia was lowered by 39%. Taira et al. (2000)reported similar benefits using voglibose. However, a recent study reported no benefit ofacarbose over placebo when both pharmaceutical and snacking interventions were comparedwith respect to their effect on preventing hypoglycaemia (Raju et al., 2006). In the light ofthese limited and conflicting data it seems unlikely that acarbose will never be widely used,particularly as sucrose-containing products cannot be used as a treatment for hypoglycaemiawhen acarbose is being taken.Pharmaceutical InterventionsThere are indications that -agonists may have some use in reducing the risk of nocturnalhypoglycaemia. For some years inhaled terbutaline has been proposed as a method ofelevating blood glucose. In the early 1990s, Wiethop and Cryer (1993) demonstrated thatits oral or subcutaneous delivery following induced hypoglycaemia, led to a rise in bloodglucose compared to placebo, an effect that lasted for some hours. More recently, Wright andWales (2003) reported that children with type 1 diabetes who were receiving treatment forasthma had fewer episodes of nocturnal hypoglycaemia when compared to a non-asthmaticgroup of children in a survey lasting three months, and they implicated a beneficial effectof -agonist therapy. Raju et al. (2006) also compared the effect of inhaled terbutaline withother therapeutic remedies such as cornstarch, standard snacks and acarbose on nocturnalblood glucose levels in patients with type 1 diabetes. They found that terbutaline preventednocturnal hypoglycaemia in all 15 subjects. However, although this treatment offered thegreatest protection against hypoglycaemia at night, it also led to the highest fasting bloodglucose among the different remedies, indicating that additional work needs to be done toestablish this treatment as a realistic therapeutic option.Timing and Type of Insulin, Including Insulin AnaloguesThe introduction of insulin analogues with pharmacokinetic properties that bear more resem-blance to physiological insulin profiles in non-diabetic individuals highlighted the potentialof such preparations to lower the risk of hypoglycaemia. Over a full 24 hours, the overallfrequency of symptomatic hypoglycaemia in trials of rapid-acting insulin analogues hasbeen modestly lower than with conventional insulins, but a consistent finding has been alower rate of nocturnal hypoglycaemia. It appears that the tendency of conventional solubleinsulin to self-associate into hexamers at therapeutic concentrations leads to increasingplasma insulin levels with repeated injection. Since rapid-acting insulin analogues separateinto single molecules much more readily, accumulation of insulin is less likely and therisk of nocturnal hypoglycaemia is subsequently lower. The frequency of nocturnal hypo-glycaemia observed in clinical trials has been variable. Rates of nocturnal hypoglycaemiahave been over 50% lower in some trials involving patients with type 1 diabetes with strict
CONCLUSIONS 95glycaemic control (Heller et al., 1999; Heller et al., 2004), and although this has generallybeen demonstrated for symptomatic episodes, these data might reflect a lower frequency ofsevere hypoglycaemia (Holleman et al., 1997).The long-acting analogues – insulins glargine and detemir – which provide basal insulinreplacement, also appear to lower the risk of nocturnal hypoglycaemia. They have a longerduration of action when compared to isophane (NPH) insulin, together with less of a peakin their time-action profile and a more consistent duration of action (Barnett, 2003). Bothof these properties probably contribute to the lower rates of nocturnal hypoglycaemia thathave been observed during clinical trials. Relative risk reductions of around 30% have beenreported for long-acting preparations in trials involving patients with type 1 (De Leeuw et al.,2005; Pieber et al., 2000) and with type 2 diabetes (Hermansen et al., 2006; Yki-Jarvinenet al., 2000).The combination of both rapid and long-acting insulin analogues might be expected to havea particularly powerful effect in lowering the risk of nocturnal hypoglycaemia. In the fewstudies comparing combinations of insulin analogues to conventional insulins this appears tobe the case. Hermansen et al. (2004) reported a 55% lower rate of symptomatic nocturnalhypoglycaemia when using an insulin detemir/aspart combination as basal-bolus therapy inpatients with type 1 diabetes, which was accompanied by a modest but significant fall in HbA1cof 0.2%. Ashwell et al. (2006) observed a fall in HbA1c of 0.5% using insulin glargine andlispro in a basal-bolus regimen in patients with type 1 diabetes, while nocturnal hypogly-caemia was 44% lower in frequency. However, nocturnal hypoglycaemia was not eradicated,leading to the conclusion that although insulin analogues may help to reduce the side-effectsof insulin therapy, they do not approach the requirements of therapeutic insulin delivery.Continuous Subcutaneous Insulin Infusion (CSII)Since nocturnal hypoglycaemia is largely the result of inadequate basal insulin replacement,one would expect that the most effective method of basal insulin delivery currently available,CSII, could limit the frequency of nocturnal hypoglycaemia (Pickup and Keen, 2002).However, early studies reported surprisingly little effect on hypoglycaemia, perhaps becauseof a failure to train patients in the essential related skills of carbohydrate and insulindose adjustment. More recent work has indicated that CSII can reduce overall rates ofhypoglycaemia (Bode et al., 1996; Boland et al., 1999; Kanc et al., 1998), but specificreporting on rates of nocturnal episodes is unusual. Furthermore, few trials have used arandomised design, suggesting that a lower risk might relate to other characteristics ofthose who use CSII rather than to the technology itself. Thus the amount to which modernpump therapy lowers the risk of nocturnal hypoglycaemia has still be to be established.Nevertheless, in those who have experienced recurrent nocturnal episodes and who have notimproved after a trial of insulin analogues, it seems worthwhile undertaking a trial of CSII.CONCLUSIONS• Nocturnal hypoglycaemia remains an unresolved clinical side-effect of insulin therapypreventing the attainment of strict glycaemic control for many people. It contributes tomorbidity, and perhaps mortality, in patients with type 1 diabetes.
96 NOCTURNAL HYPOGLYCAEMIA• Nocturnal hypoglycaemia is caused chiefly by the limitations of current methods ofinsulin delivery. The inability of subcutaneous insulin therapy, particularly conventionalbasal insulins, to maintain low-level stable insulin concentrations overnight, leads both tonocturnal hypoglycaemia and fasting hyperglycaemia.• In addition to the limitations of insulin delivery, hypoglycaemia is also more commonas a result of diminished counterregulatory responses overnight, associated in part withsleep, which has a specific inhibitory effect on physiological defences to hypoglycaemia,and a supine posture which suppresses autonomic responses.• Nocturnal hypoglycaemia is a particular problem in children, partly as a consequence ofthe long period of fasting between their evening meal and their breakfast.• The risk of nocturnal hypoglycaemia is greatest in those who have a bedtime glucosebelow 7.0 mmol/l. Bedtime snacks can reduce the risk during the early part of the night.Specific foods (uncooked cornstarch or protein rich snacks) reduce the risk of nocturnalhypoglycaemia in some studies.• Rebound hyperglycaemia (the ‘Somogyi phenomenon’) is rarely caused by counterregu-latory hormone release provoked by an overnight hypoglycaemic episode, since hormonalsecretion is generally suppressed. It is mainly a consequence of waning of circulatingplasma insulin levels and should be treated by an adjustment in the timing and type ofinsulin used rather than a reduction in insulin dose.• The problem of nocturnal hypoglycaemia may respond to the use of insulin analogues(both rapid and long-acting) or to CSII with an insulin pump. However, its eradicationwill depend upon new methods of insulin delivery.REFERENCESAshwell SG, Amiel SA, Bilous RW, Dashora U, Heller SR, Hepburn DA et al. (2006). Improvedglycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-overtrial in people with type 1 diabetes. Diabetic Medicine 23: 285–92.Banarer S, Cryer PE (2003). Sleep-related hypoglycemia-associated autonomic failure in type 1diabetes: reduced awakening from sleep during hypoglycemia. Diabetes 52: 1195–203.Barnett AH (2003). A review of basal insulins. Diabetic Medicine 20: 873–85.Bendtson I, Kverneland A, Pramming S, Binder C (1988). Incidence of nocturnal hypoglycaemia ininsulin-dependent diabetes. Acta Endocrinologica 223: 543–8.Bendtson I, Gade J, Theilgard A, Binder C (1992). Cognitive function in type 1 IDD patients afternocturnal hypoglycaemia. Diabetologia 35: 898–903.Bendtson I, Rosenfalck AM, Binder C (1993). Nocturnal versus diurnal hormonal counterregulation tohypoglycemia in type 1 (insulin-dependent) diabetic patients. Acta Endocrinologica 128: 109–15.Beregszaszi M, Tubiana-Rufi N, Benali K, Noel M, Bloch J, Czernichow P (1997). Nocturnal hypo-glycemia in children and adolescents with insulin-dependent diabetes mellitus: prevalence and riskfactors. Journal of Pediatrics 131: 27–33.Bjorgaas M, Gimse R, Vik T, Sand T (1997). Cognitive function in type 1 diabetic children with andwithout episodes of severe hypoglycaemia. Acta Paediatrica 86: 148–53.Bode BW, Steed RD, Davidson PC (1996). Reduction in severe hypoglycemia with long-term contin-uous subcutaneous insulin infusion in type I diabetes. Diabetes Care 19: 324–7.
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98 NOCTURNAL HYPOGLYCAEMIAHolleman F, Schmitt H, Rottiers R, Rees A, Symanowski S, Anderson JH, The Benelux-UK InsulinLispro Study Group (1997). Reduced frequency of severe hypoglycemia and coma in well-controlledIDDM patients treated with insulin lispro. Diabetes Care 20: 1827–32.Jones TW, Porter P, Sherwin RS, Davis EA, O’Leary P, Frazer F et al. (1998). Decreased epinephrineresponses to hypoglycemia during sleep. New England Journal of Medicine 338: 1657–62.Kalergis M, Schiffrin A, Gougeon R, Jones PJ, Yale JF (2003). Impact of bedtime snack compositionon prevention of nocturnal hypoglycemia in adults with type 1 diabetes undergoing intensive insulinmanagement using lispro insulin before meals: a randomized, placebo-controlled, crossover trial.Diabetes Care 26: 9–15.Kanc K, Janssen MM, Keulen ET, Jacobs MA, Popp-Snijders C, Snoek FJ, Heine RJ (1998). Substi-tution of night-time continuous subcutaneous insulin infusion therapy for bedtime NPH insulin in amultiple injection regimen improves counterregulatory hormonal responses and warning symptomsof hypoglycaemia in IDDM. Diabetologia 41: 322–9.Kaufman FR, Devgan S (1996). Use of uncooked cornstarch to avert nocturnal hypoglycemia inchildren and adolescents with type I diabetes. Journal of Diabetes and Its Complications 10: 84–7.Kaufman FR, Halvorson M, Kaufman ND (1997). Evaluation of a snack bar containing uncookedcornstarch in subjects with diabetes. Diabetes Research and Clinical Practice 35: 27–33.Kaufman FR, Austin J, Neinstein A, Jeng L, Halvorson M, Devoe DJ, Pitukcheewanont P (2002).Nocturnal hypoglycemia detected with the Continuous Glucose Monitoring System in pediatricpatients with type 1 diabetes. Journal of Pediatrics 141: 625–30.King P, Kong MF, Parkin H, Macdonald IA, Tattersall RB (1998). Well-being, cerebral function, andphysical fatigue after nocturnal hypoglycemia in IDDM. Diabetes Care 21: 341–5.Kulcu E, Tamada JA, Reach G, Potts RO, Lesho MJ (2003). Physiological differences betweeninterstitial glucose and blood glucose measured in human subjects. Diabetes Care 26: 2405–9.Matyka KA, Crowne EC, Havel PJ, Macdonald IA, Matthews D, Dunger DB (1999a). Counterreg-ulation during spontaneous nocturnal hypoglycemia in prepubertal children with type 1 diabetes.Diabetes Care 22: 1144–50.Matyka KA, Wigg L, Pramming S, Stores G, Dunger DB (1999b). Cognitive function and mood afterprofound nocturnal hypoglycaemia in prepubertal children with conventional insulin treatment fordiabetes. Archives of Disease in Childhood, 81: 138–42.Matyka KA (2002). Sweet dreams? Nocturnal hypoglycemia in children with type 1 diabetes. PediatricDiabetes 3: 74–81.McCulloch DK, Kurtz AB, Tattersall RB (1983). A new approach to the treatment of nocturnalhypoglycemia using alpha-glucosidase inhibition. Diabetes Care 6: 483–7.McGowan K, Thomas W, Moran A (2002). Spurious reporting of nocturnal hypoglycemia by CGMSin patients with tightly controlled type 1 diabetes. Diabetes Care 25: 1499–503.Oswald I (1987). The normal record of sleep. In: A Textbook of Clinical Neurophysiology. Halliday AM,Butler SR and Paul R, eds. John Wiley & Sons Inc., New York: 173–85.Perriello G, De Feo P, Torlone E, Calcinaro F, Ventura MM, Basta G et al. (1988). The effectof asymptomatic nocturnal hypoglycemia on glycemic control in diabetes mellitus. New EnglandJournal of Medicine 319: 1233–9.Pickup J, Keen H (2002). Continuous subcutaneous insulin infusion at 25 years: evidence base for theexpanding use of insulin pump therapy in type 1 diabetes. Diabetes Care 25: 593–8.Pieber TR, Eugene-Jolchine I, Derobert E (2000). Efficacy and safety of HOE 901 versus NPH insulinin patients with type 1 diabetes. The European Study Group of HOE 901 in type 1 diabetes. DiabetesCare 23: 157–62.Porter PA, Keating B, Byrne G, Jones TW (1997). Incidence and predictive criteria of nocturnalhypoglycemia in young children with insulin-dependent diabetes mellitus. Journal of Pediatrics130: 366–72.Pramming S, Thorsteinsson B, Bendtson I, Ronn B, Binder C (1985). Nocturnal hypoglycaemia inpatients receiving conventional treatment with insulin. British Medical Journal 291: 376–9.
REFERENCES 99Raju B, Arbelaez AM, Breckenridge SM, Cryer PE (2006). Nocturnal hypoglycemia in type 1 diabetes:an assessment of preventive bedtime treatments. Journal of Clinical Endocrinology and Metabolism91: 2087–92.Rizza RA, Gerich JE, Haymond MW, Westland RE, Hall LD, Clemens AH, Service FJ (1980).Control of blood sugar in insulin-dependent diabetes: comparison of an artificial endocrine pancreas,continuous subcutaneous insulin infusion and intensified conventional insulin therapy. New EnglandJournal of Medicine 303: 1313–18.Robinson AM, Parkin HM, Macdonald IA, Tattersall RB (1994). Physiological response to posturalchange during mild hypoglycaemia in patients with IDDM. Diabetologia 37: 1241–50.Rovet JF, Ehrlich RM (1999). The effect of hypoglycemic seizures on cognitive function in childrenwith diabetes: a 7-year prospective study. Journal of Pediatrics 134: 503–6.Ryan C, Vega A, Drash A (1985). Cognitive deficits in adolescents who developed diabetes early inlife. Pediatrics 75: 921–7.Shalwitz RA, Farkas-Hirsch R, White NH, Santiago JV (1990). Prevalence and consequences ofnocturnal hypoglycemia among conventionally treated children with diabetes mellitus. Journal ofPediatrics 116: 685–9.Somogyi M (1959). Exacerbation of diabetes by excess insulin action. American Journal of Medicine26: 169–91.Taira M, Takasu N, Komiya I, Taira T, Tanaka H (2000). Voglibose administration before the eveningmeal improves nocturnal hypoglycemia in insulin-dependent diabetic patients with intensive insulintherapy. Metabolism 49: 440–3.Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J (1993.) Induction of hypoglycemia unawarenessby asymptomatic nocturnal hypoglycemia. Diabetes 42: 1233–7.Vervoort G, Goldschmidt HM, van Doorn LG (1996). Nocturnal blood glucose profiles in patients withtype 1 diabetes mellitus on multiple (> or = 4) daily insulin injection regimens. Diabetic Medicine13: 794–9.Wentholt IM, Vollebregt MA, Hart AA, Hoekstra JB, DeVries JH (2005). Comparison of a needle-type and a microdialysis continuous glucose monitor in type 1 diabetic patients. Diabetes Care 28:2871–6.Whincup G, Milner RD (1987). Prediction and management of nocturnal hypoglycaemia in diabetes.Archives of Disease in Childhood 62: 333–7.Wiethop BV, Cryer PE (1993). Alanine and terbutaline in treatment of hypoglycemia in IDDM.Diabetes Care 16: 1131–6.Wright NP, Wales JK (2003). The incidence of hypoglycaemia in children with type 1 diabetes andtreated asthma. Archives of Disease in Childhood 88: 155–6.Yki-Jarvinen H, Dressler A, Ziemen M (2000). Less nocturnal hypoglycemia and better post-dinnerglucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulincombination therapy in type 2 diabetes. HOE 901/3002 Study Group. Diabetes Care 23: 1130–6.
102 MODERATORS, MONITORING AND MANAGEMENTTable 5.1 Causes of hypoglycaemia in patients with diabetesChange in insulinsensitivityChange in insulinpharmaco-dynamicsAltered insulin:carbohydrate ratio Other related conditions‘Honeymoon period’in newly diagnosedtype 1 diabetesChange in injection site Unplanned exercise Endocrine dysfunction(Addison’s disease,hypopituitarism)Post-partum Change in insulinformulationChange in socialcircumstancesPsychologicalMenstruation Change in temperature BreastfeedingAlcohol GastroparesisRenal failure Malabsorption e.g.Coeliac DiseaseExercise• ambient temperature;• psychological factors such as mood;• use of other medicines affecting skin blood flow;• for pre-mixed insulin preparations – whether the insulin has been shaken adequately beforethe injection.Although there is now greater awareness of the importance of educating patients aboutthe nuances of dietary carbohydrate counting, it is important to remember that the absorptionof food is also variable within individuals, being affected by the constituents and size of ameal, and the speed with which it is eaten. In addition, gastric emptying is variable withinan individual with diabetes and is influenced by the status of the autonomic nervous system(Feldman and Schiller, 1983; Vinik et al., 2003).In addition, improving glycaemic control and lowering HbA1c per se are also associatedwith a trebling of risk for hypoglycaemia (The Diabetes Control and Complications TrialResearch Group, 1995). However, this alone does not wholly predict the occurrence ofhypoglycaemia. In the intensively treated group in the DCCT, HbA1c only accounted for60% of the risk of severe hypoglycaemia (The Diabetes Control and Complications TrialResearch Group, 1997). Additional risk factors have also been identified, many of which arediscussed in detail in Chapter 3:• previous episodes of severe hypoglycaemia (Bott et al., 1997; The Diabetes Control andComplications Trial Research Group, 1997);• long duration of type 1 diabetes (Cox et al., 1994; The Diabetes Control and ComplicationsTrial Research Group, 1997);• intensive insulin therapy (The DCCT Research Group, 1991);• strict glycaemic control (The Diabetes Control and Complications Trial Research Group,1997);
LIFESTYLE MODERATORS 103• absolute insulin deficiency (Bott et al., 1997; The Diabetes Control and ComplicationsTrial Research Group, 1997);• sleep (Pramming et al., 1990; The Diabetes Control and Complications Trial ResearchGroup, 1997);• impaired hypoglycaemia awareness (Gold et al., 1994);• alcohol (Richardson et al., 2005b);• exercise (MacDonald, 1987);• pregnancy (Rosen et al., 1995);• impaired renal function (Muhlhauser et al., 1991).Despite these risk factors being recognised, it is often difficult to untangle the majorprecipitating factors for a given episode of severe hypoglycaemia. Patient recall is oftenvague, preconceptions may have been applied and amnesia for an event is common. Anec-dotally, around a third to half of episodes remain unexplained in routine clinical practice,although patient ‘error’ is still perceived (by healthcare professionals) as the most likely‘cause’ of a hypoglycaemic episode (The DCCT Research Group, 1991).LIFESTYLE MODERATORSNumerous lifestyle influences predispose towards hypoglycaemia, and some of these, suchas pregnancy (Chapter 10) and exercise (Chapter 14), are discussed elsewhere in this book.Alcohol and HypoglycaemiaAlcohol is an important risk factor for hypoglycaemia for individuals treated with insulin,with estimates suggesting that up to 20% of severe hypoglycaemic events are attributableto its use (Potter et al., 1982; Nilsson et al., 1988). However, there is nothing to suggestthat (in general terms) people with type 1 diabetes adopt a different approach to their use ofalcohol than the rest of the population.Alcohol has been associated with hypoglycaemia in several ways:• Ingestion of even small amounts may impair the ability of the individual to detect theonset of hypoglycaemia at a stage when they are still able to take appropriate action, i.e.,eat some carbohydrate.• Hypoglycaemia per se may be mistaken for intoxication by observers, with legal andhealth consequences.• Alcohol has been shown in some studies to impact directly on gluconeogenesis and/or thecounterregulatory responses to hypoglycaemia (Turner et al., 2001; Kerr et al., 2007).• Recent data indicate that small amounts of alcohol can augment the cognitive deficitassociated with hypoglycaemia in individuals with type 1 diabetes (Cheyne et al., 2004).
104 MODERATORS, MONITORING AND MANAGEMENTIn the past, biochemical hypoglycaemia (in non-diabetic individuals) associated withalcohol intoxication was attributed to the toxic effects of impurities associated with theproduction of illicit drinks (‘hooch’ or ‘moonshine’). These included methanol, gasoline andethyl acetate (Brown and Harvey, 1941). More recently, it was thought that the biochemicaleffects of alcohol were associated with hypoglycaemia in three ways:• inhibition of gluconeogenesis;• potentiation of the effects of exercise and glucose-lowering agents;• causing reactive hypoglycaemia in susceptible individuals.More than 90% of an ethanol load is metabolised by the liver, being catalysed by alcoholdehydrogenase into acetate. The rate-limiting step is ultimately dependent upon the avail-ability of nicotinamide di-nucleotide (NAD+) in a glycogen-replete state. In conditionswhere glycogen stores are depleted and blood glucose is being maintained by hepatic glucoseproduction (e.g. in malnourished individuals and after prolonged exercise), alcohol inges-tion may lead directly to a fall in blood glucose. In contrast, studies have failed to showany short-term effect of alcohol consumed with a meal (Kerr et al., 1990; Avogaro et al.,1993), or when given intravenously after an overnight fast (Kolaczynski et al., 1988). This isprobably because the suppression of gluconeogenesis by ethanol has little effect on hepaticglucose output in well-fed subjects (Gin et al., 1992) and may in fact be counterbalancedby a reduction in peripheral glucose uptake (Koivisto et al., 1993). In well-nourished, non-diabetic subjects, very little evidence is available to suggest that alcohol has any significanteffect on glucose homeostasis (Trojan et al., 1999).However, alcohol has been shown to suppress lipolysis acutely (Avogaro et al., 1993).Following ingestion of alcohol, a reduction in plasma levels of free fatty acids is associ-ated with a reduction in gluconeogenesis and an increased risk of hypoglycaemia in type1 diabetes (Avogaro et al., 1993). In other words, any potential effect of alcohol uponprevailing glucose is likely to be maximal at a time when glucose homeostasis is dependentupon free fatty acid production, e.g. overnight, when lipolysis increases to promote gluco-neogenesis (Hagstrom-Toft et al., 1997). The alcohol-induced suppression of lipolysis maythen predispose to hypoglycaemia the next morning (Figures 5.1 and 5.2). The predispositionto delayed hypoglycaemia in type 1 diabetes may be augmented by relative hyperinsuli-naemia, which in turn further suppresses lipolysis. However, it is likely that other factorsare involved, as in well-fed subjects the suppression of gluconeogenesis by alcohol per semay have little effect on hepatic glucose output (Gin et al., 1992), and is considered to becounterbalanced by a reduction in peripheral glucose uptake (Koivisto et al., 1993).In a clinical context the main concern for insulin-treated individuals is that moderatealcohol intake (6–9 units) can acutely diminish hypoglycaemia awareness (Moriarty et al.,1993) and impair counterregulatory responses to insulin-induced hypoglycaemia (Yki-Jarvinen and Nikkila, 1985; Pukakainen et al., 1991). Glucagon release has been shown tobe suppressed by alcohol in some studies (Rasmussen et al., 2001), but not in others (Kerret al., 1990). However, the prolonged hypoglycaemic effect of alcohol following its ingestionis more likely to implicate either cortisol or growth hormone responses to hypoglycaemia(Figure 5.3). In animal studies, alcohol has been shown to stimulate corticotrophin-releasinghormone and thus increase plasma cortisol (Rivier et al., 1984). A rise in circulating gluco-corticoid can inhibit growth hormone release (Wehrenberg et al., 1990), which in turn may
LIFESTYLE MODERATORS 10520 22 24 2 4 6 8 10 12 14TimeAdrenaline FFA Growth Hormone GlucoseFigure 5.1 Pictoral showing steady nocturnal and next-day glucose concentrations, a normal rise ingrowth hormone and free fatty acids overnight, and a normal counterregulatory response should therebe a predisposition to hypoglycaemia20 22 24AlcoholPotential forhypoglycaemia2 4 6 8 10 12 14TimeFFA GlucoseGHAdrenalineFigure 5.2 Pictoral indicating a slow decline in plasma glucose following evening alcohol ingestion,suppression of free fatty acids and overnight growth hormone release, and the inability to counterreg-ulate an increased predisposition to hypoglycaemia and impaired awareness of hypoglycaemiabe further reduced through the direct inhibition of growth hormone release through the acuteingestion of alcohol (Conway and Mauceri, 1991).In type 1 diabetes, the influence of alcohol ingestion on the immediate counterregu-latory responses has been investigated by a hyperinsulinaemic clamp study (Kerr et al.,2007). Ingestion of modest amounts of alcohol (to plasma levels of less than 50 mg/dl)
106 MODERATORS, MONITORING AND MANAGEMENTFree insulin (pmol/l)WineWaterWineWaterWineWaterWineWaterCortisol (nmol/l)Growth hormone (µg/l) Glucagon (ng/l)Time (24 h)500400300200100080070060050040030020010003.53.02.52.01.51.00.50.0908070605040302010020 22 24 02 04 06 08 10 12Time (24 h)20 22 24 02 04 06 08 10 12Time (24 h)20 22 24 02 04 06 08 10 12Time (24 h)20 22 24 02 04 06 08 10 12Figure 5.3 Counterregulatory hormone responses following earlier ingestion of alcohol indicatingsuppression of overnight growth hormone secretion. Reproduced from Turner et al., 2001, withpermission from The American Diabetes Associationappears to attenuate the usual growth hormone response to mild hypoglycaemia (Figure 5.4).Other investigators have reported that acute and sustained alcohol ingestion in non-diabeticsubjects can suppress growth hormone release in response to insulin-induced hypoglycaemia(Kolaczynski et al., 1988; Kerr et al., 1990), and also in individuals suffering from reactivehypoglycaemia (Avogaro et al., 1993). In association with blunting of the hormonal counter-regulatory responses to hypoglycaemia following alcohol ingestion, insulin sensitivity alsoappears to be increased (Ting and Lautt, 2006), thus perhaps directly suppressing hepaticglucose production.Recent studies have also reported blunting of the epinephrine response to hypoglycaemiaafter alcohol (Figure 5.5). The reduction is catecholamine response was mirrored by areduction in hypoglycaemia awareness, which has been described previously with alcohol(Kerr et al., 1990).This blunting of the adreno-medullary response could result from a number of differentmechanisms:• Antecedent nocturnal hypoglycaemia could predispose to delayed hypoglycaemia(Veneman et al., 1993) (i.e., hypoglycaemia leads to more hypoglycaemia).• Sleep patterns are altered by alcohol, which may increase the time spent in ‘deep’ non-REMsleep, thereby increasing the predisposition towards hypoglycaemia through a reductionin the ability to counterregulate (Jones et al., 1998) (see Chapter 4).
LIFESTYLE MODERATORS 107Growth hormone (mean and SE)051015202530350 30 60 90 120 150 180 210 240Time (mins)Growthhormone(µg/l)E + PE + AH + PH + AGlc = 4.5 Glc = 4.5 / 2.8 Glc = 4.5alcoholFigure 5.4 Growth hormone concentrations during the four study conditions (E = euglycaemia,P = placebo, H = hypoglycaemia, A = alcohol and Glc = glucose)Plasma adrenaline during hyperinsulinaemic hypoglycaemic clampAlcohol PlaceboBaseline euglycemia4.5mmol/lInitial hypoglycaemia2.5mmol/lEnd hypoglycaemia2.5mmol/lEuglycaemia4.5mmol/lAdrenaline(ng/ml)120010008006004002000Figure 5.5 Epinephrine (adrenaline) response during a hypoglycaemic clamp following alcoholingested 12 hours previously (unpublished data of authors)
108 MODERATORS, MONITORING AND MANAGEMENT• Other mechanisms, which could account for a failure to counterregulate through an inade-quate catecholamine response, could be explained by a reduction in GH-associated primingof the catecholamine response.The blunted catecholamine response to hypoglycaemia may explain why symptom scoresare lower; this may account for the previously described, alcohol-induced impairment ofhypoglycaemia awareness that is associated with delayed hypoglycaemia following consump-tion of alcohol at an earlier time (Kerr et al., 1990).The predisposition of alcohol to cause prolonged, recurrent hypoglycaemia with bluntingof the counterregulatory response, may lead to delayed hypoglycaemia and impaired aware-ness of hypoglycaemia. Knowledge of the increased risks and dangers involved with anincreased risk of severe hypoglycaemia is important so that patients can make appropriateadjustments to their lifestyles.Although patients often ask for guidance about alcohol and diabetes, the advice offeredcan be variable and conflicting. For people treated with insulin, it is often recommendedthat dietary carbohydrate should not be omitted and alcohol should be taken with, or shortlybefore, food. Patients should be advised that the risk of hypoglycaemia may extend for‘several hours’ after drinking. It is an important clinical observation that, at blood alcohollevels that remain within the statutory limits for driving in the UK, autonomic and neuro-glycopenic warning symptoms of early hypoglycaemia can be impaired and the cognitivedeficits that are usually associated with mild hypoglycaemia are augmented (Cheyne et al.,2004). As is recommended for all non-diabetic drivers, the advice should be to consume noalcohol if an individual is planning to drive.A further consideration is the ‘morning after the night before’ phenomenon in terms ofhypoglycaemia risk. In a laboratory-based study, Turner et al. (2001) reported that ingestionof alcohol with an evening meal increased the risk of hypoglycaemia the next morning(Figure 5.6). More recently, a study of people with type 1 diabetes during their normal dailylives and using a continuous glucose monitoring system (CGMS), confirmed a predispositionWineWaterGlucose(mmol/l)Time (24 h)18 20 22 24 02 04 06 08 10 12201612840Figure 5.6 Change in overnight plasma glucose following alcohol or placebo (Turner et al., 2001).The period of drinking is indicated by the shaded bar and the times of symptomatic hypoglycaemia areindicated by the vertical arrows. Reprinted with permission from The American Diabetes Association
LIFESTYLE MODERATORS 109–5.0–4.0–3.0–2.0–1.00.01.02.03.018:00 20:00 22:00 00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00meanchangeininterstitialglucose(mmol/l)period of increasedrisk ofhypoglycaemiaFigure 5.7 Mean difference in interstitial glucose between alcohol and placebo beverages followingstandardised meal at 19:00–20:00to delayed hypoglycaemia (Richardson et al., 2005b). In this study alcohol was shown toreduce average interstitial tissue glucose (Figure 5.7) and increase the risk of hypoglycaemiaover the following 24 hours, with patients reporting more than twice as many hypoglycaemicepisodes per day.In the study of Richardson et al. (2005b), the average interstitial glucose level was 1–2 mmol/l lower with alcohol, but the rate of hypoglycaemia the next day depended on theprevailing levels of glucose overnight. Patients who had a lower baseline glucose at thebeginning of the night or in the morning, were at a greater risk of developing alcohol-inducedhypoglycaemia than those with preceding hyperglycaemia. This increased risk persisted fornearly a full day after alcohol ingestion (Richardson et al., 2005b).CaffeineThe consumption of caffeine has occurred for over 8000 years. Its impact on health –both good and bad – has been widely reported and disputed. Coffee (and caffeine) is themost widely used stimulant in the world and is consumed by more than 50% of Britonsregularly. This amounts to about 75 million cups of coffee consumed every day. Caffeineis also consumed in a variety of different formats such as tea and soft drinks and in ‘overthe counter’ remedies for coughs and colds. During the period from 1960 to 1982, thelevel of consumption of caffeine-containing products rose by 231% (Gilbert, 1984), andin the UK, the average caffeine consumption by adults was estimated to be 400 mg daily(Gilbert, 1984). Children, who do not drink coffee, may consume equivalent amounts insoft drinks.Caffeine exerts a variety of pharmacological actions at diverse sites, both centrallyand peripherally, principally through adenosine receptor antagonism. Although it has beensuggested that the amount of caffeine consumed is related to the risk of developing orprotecting against type 2 diabetes (Pereira et al., 2006), the discussion here is focused onthe influence that caffeine has on the physiological responses to a fall in blood glucose.
110 MODERATORS, MONITORING AND MANAGEMENT04080120160200DayplaceboDaycaffeineNightplaceboNightcaffeineMinutesofinterstitialhypoglycaemiaFigure 5.8 Diurnal variation in time spent in hypoglycaemic range (interstitial glucose <3 5mmol/l)comparing caffeine and placebo. Error bars indicate the confidence intervals of the meansPrevious studies have shown that ingestion of moderate amounts of caffeine may be usefulby augmenting the symptomatic and hormonal responses to mild hypoglycaemia. Caffeine(3–4 cups of drip-brewed coffee each day) enhances the symptomatic and sympathoadrenalresponses to hypoglycaemia in healthy non-diabetic volunteers and in patients with type 1diabetes (Kerr et al., 1993; Debrah et al., 1996). This may enhance the ability of individualsto perceive the onset of symptoms and take appropriate action by ingesting carbohydratebefore neuroglycopenia develops. The beneficial effect of caffeine on hypoglycaemia risk isindependent of a change in glycaemic control (Watson et al., 2000). Putative mechanismshave included an increase in counterregulatory hormones, including epinephrine, growthhormone and cortisol, but not norepinephrine (Debrah et al., 1996).More recently the influence of caffeine on frequency of hypoglycaemia in patients withlong-standing type 1 diabetes has been studied using CGMS. By using continuous monitoring,caffeine appears to reduce the duration of nocturnal hypoglycaemia in subjects with type 1diabetes by almost 50% (Richardson et al., 2005a) (Figure 5.8). It has been suggested thata beneficial effect of the caffeine-associated reduction in nocturnal hypoglycaemia may beto reduce the risk of developing impaired awareness of hypoglycaemia on the next day. Thecaffeine-associated reduction in ‘antecedent’ nocturnal hypoglycaemia seen in these studiesmay explain the augmentation in the symptomatic and hormonal responses to mild daytimehypoglycaemia described previously (Debrah et al., 1996).The relationship between autonomic dysfunction and the development of impaired aware-ness of hypoglycaemia was unclear for many years (see Chapter 7). Most studies havesuggested that peripheral autonomic neuropathy is not associated with an increased riskof severe hypoglycaemia (Polinsky et al., 1980; Bjork et al., 1990; Ryder et al., 1990;The DCCT Research Group, 1991) although central autonomic dysfunction may be impor-tant (Evans et al., 2003). Although caffeine improves parasympathetic autonomic function(Richardson et al., 2004), no correlation was found with the observed reduction in nocturnalhypoglycaemia associated with caffeine. As mentioned earlier, it is possible that caffeineuncouples cerebral blood flow and glucose utilisation via antagonism of adenosine receptors(Laurienti et al., 2003), attenuating the glucose supply to the brain (reduced cerebral blood
MONITORING 111flow) while simultaneously increasing glucose demand, thus resulting in relative neurogly-copenia and earlier release of counterregulatory hormones.Caffeine may also act through an alteration in sleep pattern as adenosine has been impli-cated in the physiological regulation of sleep. Caffeine reduces non-rapid eye movement(REM) sleep (Landolt et al., 1995), a stage of sleep that is associated with attenuatedcounterregulatory responses to hypoglycaemia (Jones et al., 1998). Therefore, it couldbe hypothesised that caffeine reduces the time spent in non-REM sleep, lessening theperiod during which counterregulatory responses are suppressed. This may protect againstprolonged hypoglycaemia and may explain the findings of fewer and shorter moderateepisodes of nocturnal hypoglycaemia in people using caffeine. The suggested beneficialeffects of caffeine on nocturnal hypoglycaemia would support the notion that caffeineuse should be encouraged in a population that is prone to the risks of severe nocturnalhypoglycaemia.MONITORINGIt is a sine qua non that the best defence against hypoglycaemia is the ability to recogniseit at an early stage and take appropriate action. Nevertheless, some people lose their abilityto detect hypoglycaemia:• Individuals may fail to develop appropriate warning symptoms.• Individuals may fail to recognise the warning symptoms as being related to hypoglycaemia.• Individuals may recognise the warning symptoms but may be unable to take appropriateaction because of neuroglycopenia.Memory impairment is commonly associated with hypoglycaemia (see Chapter 2) andthus patient recall may underestimate the true frequency of the problem. Furthermore thedefinition of hypoglycaemia needs to be agreed by the patient, their relatives and their healthprofessionals especially for more modest events, which are often ‘accepted’ by patients asan inevitable part of insulin treatment.As a consequence, it is important that patients have additional methods of detecting lowblood glucose levels. Invariably this involves finger stick measurements of blood glucoselevels using glucose meters. However, this method has problems per se related to:• poor technical performance, e.g. inadequate samples;• contamination (actually rare in routine practice);• technical limitations of the devices (Melki et al., 2006).Recently novel methods for measuring glucose levels have been introduced although atpresent none fulfils the ‘holy grail’ of non-invasive glucose monitoring. It is noteworthythat the newer methods of measuring interstitial glucose have highlighted the fact thathypoglycaemia remains a common problem in type 1 diabetes management and that manyepisodes remain unrecognised (Cheyne and Kerr, 2002). These methods can, however, be auseful aid, allowing patients (and their healthcare professionals) to determine the modulating
112 MODERATORS, MONITORING AND MANAGEMENTSensor Profile – before pump therapy0.05.010.015.020.025.00:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00TimeSensorvalue(mmol/l)Sensor Profile – after pump therapy0.05.010.015.020.025.00:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00TimesensorvalueFigure 5.9 CGMS profile before and after conversion to CSII in a patient with > 15 years of poorlycontrolled type 1 diabetes0.05.010.015.020.00:00 4:00 8:00 12:00 16:00 20:00 24:00TimeGlucoseConcentration(mmol/L)Figure 5.10 CGMS profile indicating the extent of postprandial hyperglycaemia. Capillary bloodglucose measurements are shown in square boxesinfluence of a number of factors on glycaemic control and insulin use (Figures 5.9 and 5.10).Unfortunately they have a number of limitations, as detailed in the next section.Continuous Glucose Monitoring Systems (CGMS)There are limitations to the use of traditional blood glucose measurements for detectinglow blood glucose levels. Consequently, a great deal of time, effort and money has beenspent on developing new methods for the detection of low blood glucose levels. The mostpopular system at present is the use of a continuous glucose monitoring system (CGMS)(Hoi-Hansen et al., 2005). However, technical considerations influence the use of interstitialglucose monitoring for the detection of hypoglycaemia, specifically:• There is a physiological lag between changes in blood and interstitial glucose levels whichsuggest that CGMS may overestimate the duration of a hypoglycaemic event.• It is unclear as to the significance of changes at the level of interstitial fluid compared tofluctuations in blood glucose level.
MONITORING 113• It is unclear whether changes in interstitial glucose levels, measured in the anteriorabdominal wall, mirror those occurring at the level of glucose sensing neurones in thehypothalamus and elsewhere.• The recordings from the CGMS are markedly influenced by the accuracy and frequencyof the results of fingerstick blood testing for calibration purposes.The first commercially available device, the CGMS (Medtronic Minimed, Minneapolis,USA), was designed to monitor glucose levels continuously in tissue fluid. The systemcomprised a disposable subcutaneous glucose sensor connected by a cable to a pager-sizedglucose monitor. The sensor measured interstitial glucose levels every 10 seconds andaveraged over 5 minutes, i.e., 288 measurements each day, and provided measurementsof glucose in the range of 2.2–22 mmol/l. The first version provided retrospective data.The latest generation sensor transfers data to an on-screen display in real-time for thepatient to adjust his or her own medication (Bode et al., 2004). One problem has been indefining hypoglycaemia using these devices, although some groups have defined interstitialhypoglycaemia according to the level at which there is activation of the counterregulatoryhormone cascade and onset of neuroglycopenic symptoms respectively (Fanelli et al., 1994)(Table 5.2).There are also other limitations (including expense) in the use of continuous interstitialmonitoring devices. Continuous glucose monitoring is a technique in its infancy and as suchthere is debate whether it has the ability to detect ‘true’ hypoglycaemia (McGowan et al.,2002). This uncertainty relates to a number of factors including:Table 5.2 Guidelines for interpreting interstitial hypoglycaemia using CGMS as devel-oped by the UK Hypoglycaemia Study Group (2007), and published in Department forTransport Road Safety Research Report No. 61, “Stratifying hypoglycemic event risk ininsulin-treated diabetes” (2006), pp. 68–9Defining an episode of hypoglycaemiaThere must be four consecutive readings of 3.5 mmol/l or lower for an episode to beclassified as hypoglycaemia.The first of the readings (of 3.5 mmol/l or less) signifies the start of hypoglycaemia.The first reading of 3.5 mmol/l or above signifies the end of hypoglycaemia.Hypoglycaemia ends fully when there are four or more consecutive readings above3.5 mmol/l.If during hypoglycaemia the sensor value is 3.5 mmol/l or higher for 1–3 readings andthen goes back down below 3.5 mmol/l, then the whole episode is counted as onehypoglycaemic event and the short period above 3.5 mmol/l is included in theduration of hypoglycaemia.To be labelled as moderate hypoglycaemia, the sensor has to read 3.0 mmol/l orbelow for at least four consecutive readings.If during mild hypoglycaemia the reading falls to 3.0 mmol/l or below for four ormore consecutive readings, the whole hypoglycaemic episode will be considered asmoderate hypoglycaemia.Prolonged hypoglycaemia is defined as lasting > 2 hours.
114 MODERATORS, MONITORING AND MANAGEMENTSensor value compared to blood glucose0.001.002.003.004.005.006.000:00 1:00 2:00 3:00 4:00Time (hours)Glucose(mmol/l)sensor averageaverage BGFigure 5.11 Comparison between interstitial (CGMS) and plasma glucose under hyperinsulinaemichypoglycaemic clamp conditions• the potential error in recording glucose values at the limit of the detection range;• the potential for artefact (a flat line might indicate a low glucose value or a technicalproblem with the recording);• differences between blood and extracellular interstitial glucose.Continuous glucose monitoring methodology does not directly sample blood glucosebut records glucose values in the extracellular interstitial space. Glucose diffuses acrossthe capillary wall into the interstitial space before being transported into cells where it ismetabolised or stored. The relationship between blood and interstitial glucose is not wellunderstood and there are physiological and pharmacological reasons why the two may differ.Laboratory studies have demonstrated a variable relationship between blood and interstitialglucose concentrations according to whether blood glucose is falling or rising, and circulatinginsulin concentrations may also be important (Caplin et al., 2003).Finally, it is important to note that the use of CGMS is best used to corroborate themore traditional method of recording hypoglycaemia events, which is relying on patients’self-reports. Even taking into account the uncertainty of which CGMS value representstrue hypoglycaemia, rates of low glucose are comparable whether measured by prospectivecollection of self-reported episodes or by continuous glucose monitoring.Although there is increasing experience with the CGMS system for detection of hypogly-caemia, the relationship between interstitial glucose levels measured from the anterior abdom-inal wall and cerebral interstitial levels is unknown. Furthermore, in non-diabetic individuals,the CGMS may overestimate the duration of hypoglycaemia as there appears to be a timelag between sensor-measured interstitial tissue glucose and peripheral blood glucose levelsduring recovery from hypoglycaemia (Cheyne et al., 2002) (Figure 5.11). Overestimation ofnocturnal hypoglycaemia in patients with strictly controlled type 1 diabetes has also beenreported (McGowan et al., 2002). However, in more customary populations where capillaryglucose sensor calibration was more widely dispersed, accurate prediction of hypoglycaemiawith the CGMS has been demonstrated (McGowan et al., 2002; Caplin et al., 2003).
MANAGEMENT OF HYPOGLYCAEMIA 115MANAGEMENT OF HYPOGLYCAEMIAIt goes without saying that prevention is better than cure and patients with diabetes needto be thoroughly and continuously educated about the potential risks of hypoglycaemia.Diabetes UK recommends a policy of 4 is the floor as a capillary blood glucose level forintervention with regard to treating hypoglycaemia. The treatment of hypoglycaemia is bestregarded as a spectrum of increasing intervention with at one end the simple ingestion of oralcarbohydrate and at the other, acute medical therapy in an intensive care unit (Table 5.3).The simplest treatment, when the patient recognises the early warning symptoms (seeChapter 2), is to eat carbohydrate, which must be palatable, concentrated and portable.Glucose tablets (Dextrosol) are usually recommended in the UK, barley sugar in the USAand, in France, lumps of sugar (sucrose). Beverages such as soft drinks or orange juicewith a high glucose content are also suitable. The important factor is that short-actingcarbohydrate should be followed by some form of longer-acting carbohydrate such as bread orbiscuits.The second level of treatment is when the patient is clearly hypoglycaemic but cannotor will not take oral fast-acting carbohydrate. People on insulin will often not admit tobeing hypoglycaemic and may react adversely to attempts to give them carbohydrate. Liquidglucose solutions are often unsatisfactory because the patient can spit them out. It is betterto use a commercially-available glucose gel such as GlucoGel (Diabetic Bio-diagnostics),which can be squeezed like toothpaste into the mouth and is absorbed through the buccalmucosa. Although some doubts have been expressed about the effectiveness of oral glucosegels, relatives often seem to prefer to try this before resorting to injecting glucagon. It shouldnot be used in semi-comatose patients or those at risk of aspirating. Jam or honey may bejust as effective.Glucagon promotes hepatic glycogenolysis and the glycaemic response to a dose of1 mg is essentially the same whether it is injected subcutaneously, intramuscularly or intra-venously (Muhlhauser et al., 1985a). The advantage of glucagon is that it can be givenTable 5.3 The therapeutic spectrum of hypoglycaemia; complexity of treatment depends primarilyon duration (adapted from MacCuish, 1993)Duration of hypoglycaemiaInitial Management(minutes)Ongoingmanagement (hours)By patient By family By paramedicsIn hospital A&Edepartment In intensive careOral carbohydrate(> 20g)Oral carbohydrate(liquid/solid)Glucagon 1mgim or iv25 g glucose iv Mannitol (20%,20 ml)Glucagon 1 mg iv DexamethasoneGlucose gel 25 g glucose iv Dextrose/insulininfusionGlucagon 1 mg im OxygenAnticonvulsantsSedation
116 MODERATORS, MONITORING AND MANAGEMENTby relatives or friends after minimal training. Paramedics can also use it at the patient’shome or in an ambulance. The disadvantages are that it takes longer (approximately 10minutes) than intravenous glucose to restore consciousness and does not work in patientswho have deficient or absent hepatic glycogen stores (alcoholics or people with cachexia).Unfortunately, even where glucagon is available, relatives or friends may not use it. Inone study (Muhlhauser et al., 1985b), 53 of 123 episodes of severe hypoglycaemia weretreated by relatives or friends with glucagon, 30 by assisting physicians and 44 requiredhospital admission. When glucagon was available but not used, it was because those whoknew how to use it were not present (20 cases) or were too anxious to do so (24 cases).In children with diabetes, Daneman et al. (1989) found that glucagon was used in only athird of households in which it was available – presumably because relatives were eithertoo frightened or poorly educated. Another problem is the limited shelf life; Ward et al.(1990) found that nearly three-quarters of patients knew about glucagon but only 20% hada supply that was in date. Its effect is less certain if coma has been prolonged. In a studyof 100 patients brought to a hospital outpatient department, glucagon was immediatelyeffective in only 41% of patients whose mean estimated duration of coma was 50 minutes(MacCuish et al., 1970).Within five minutes the traditional dose of 50 ml of a 50% glucose (dextrose) solutionraises blood glucose from below 1 to > 12mmol/l (Collier et al., 1987). This dose isnow considered to be too large by using too concentrated a solution, and 20% dextrosewill suffice. The main problem is the difficulty of giving an intravenous injection toan uncooperative patient who may be refusing or resisting treatment or who has to bephysically restrained to receive an intravenous injection. Extravasation of the concen-trated glucose solution outside the vein causes painful phlebitis and, because of its hyper-tonicity, even an intravascular injection can cause phlebitis or thrombosis. It is not there-fore used much outside hospitals, and few GPs carry glass vials of dextrose for thispurpose.When a patient known to have type 1 diabetes is admitted to hospital in hypogly-caemic coma, but fails to recover after being given intravenous glucose, other causes ofcoma such as excessive ingestion of alcohol, self-poisoning with opiates or other drugs,acute vascular events such as subarachnoid haemorrhage or stroke, head injury or otherintracranial catastrophes must be excluded. Cerebral oedema is a recognised sequel ofsevere hypoglycaemia, and urgent neuroimaging is required to establish its presence; treat-ment (Table 5.3) is usually in an intensive care unit as this complication has a highmortality.The most difficult decision is to know for how long to continue treatment. Patients,who have made a full recovery after being unconscious for several days, may (anecdotally)appear subsequently to have significant cognitive impairment or permanent brain damage.It is beyond the scope of this chapter to discuss the investigation and management ofhypoglycaemia in non-diabetic individuals.In conclusion, hypoglycaemia continues to be a common problem in the management ofindividuals with type 1 diabetes. The use of newer technologies of continuous glucose moni-toring has highlighted that it is almost impossible to eliminate hypoglycaemia completelywith present insulin therapy, although understanding moderating factors such as alcohol andincluding them as a component of education programmes for people with insulin-treateddiabetes may help to alleviate some of the anxiety associated with the risk of living constantlywith the threat of hypoglycaemia.
REFERENCES 117CONCLUSIONS• Hypoglycaemia is associated with multiple risk factors.• Alcohol is a frequent cause of severe hypoglycaemia.• Alcohol is associated with delayed hypoglycaemia through impaired hypoglycaemiaawareness and an abnormal counterregulatory response.• Understanding of the nature of alcohol-associated hypoglycaemia is the first step toreducing the risks associated with alcohol.• Caffeine may augment the symptomatic and hormonal responses to hypoglycaemia andreduce nocturnal hypoglycaemia in individuals with type 1 diabetes.• Continuous Glucose Monitoring is a useful adjunct to the management of the patient withtype 1 diabetes.• Treatment of hypoglycaemia can be regarded as a spectrum of increasing therapeuticcomplexity depending on the severity of the hypoglycaemia and the clinical status of thepatient.REFERENCESAvogaro A, Beltramello P, Gnudi L, Maran A, Valerio A, Miola M et al. (1993). Alcohol intakeimpairs glucose counterregulation during acute insulin-induced hypoglycemia in IDDM patients.Evidence for a critical role of free fatty acids. Diabetes 42: 1626–34.Bjork E, Palmer M, Schvarcz E, Berne C (1990). Incidence of severe hypoglycaemia in an unselectedpopulation of patients with insulin-treated diabetes mellitus, with special reference to autonomicneuropathy. Diabetes Nutrition and Metabolism 4: 303–9.Bode B, Gross K, Rikalo N, Schwartz S, Wahl T, Page C et al. (2004). Alarms based on real-timesensor glucose values alert patients to hypo- and hyperglycemia: the guardian continuous monitoringsystem. Diabetes Technology and Therapeutics 6: 105–13.Bott S, Bott U, Berger M, Muhlhauser I (1997). Intensified insulin therapy and the risk of severehypoglycaemia. Diabetologia 40: 926–32.Brown TM, Harvey AM (1941). Spontaneous hypoglycemia in ‘smoke’ drinkers. Journal of theAmerican Medical Association 17: 12–5.Caplin NJ, O’Leary P, Bulsara M, Davis EA, Jones TW (2003). Subcutaneous glucose sensor valuesclosely parallel blood glucose during insulin-induced hypoglycaemia. Diabetic Medicine 20: 238–41.Cheyne EH, Cavan DA, Kerr D (2002). Performance of a continuous glucose monitoring system duringcontrolled hypoglycemia in healthy volunteers. Diabetes Technology and Therapeutics 4: 607–13.Cheyne E, Kerr D (2002). Making ‘sense’ of diabetes: using a continuous glucose sensor in clinicalpractice. Diabetes Metabolism Research and Reviews 18 Suppl 1: S43–8.Cheyne EH, Sherwin RS, Lunt MJ, Cavan DA, Thomas PW, Kerr D (2004). Influence of alcoholon cognitive performance during mild hypoglycaemia; implications for type 1 diabetes. DiabeticMedicine 21: 230–7.Collier A, Steedman DJ, Patrick AW, Nimmo GR, Matthews DM, MacIntyre CA et al. (1987).Comparison of intravenous glucagon and dextrose in treatment of severe hypoglycemia in anAccident and Emergency Department. Diabetes Care 10: 712–5.Conway S, Mauceri H (1991). The influence of acute ethanol exposure on growth hormone release infemale rats. Alcohol 8: 159–64.
118 MODERATORS, MONITORING AND MANAGEMENTCox DJ, Gonder-Frederick L, Julian DM, Clarke W (1994). Long-term follow-up of blood glucoseawareness training. Diabetes Care 17: 1–5.Daneman D, Frank M, Perlman K, Tamm J, Ehrlich R (1989). Severe hypoglycemia in children withinsulin-dependent diabetes mellitus: frequency and predisposing factors. Journal of Pediatrics 115:681–5.Debrah K, Sherwin RS, Murphy J, Kerr D (1996). Effect of caffeine on recognition of and physiologicalresponses to hypoglycaemia in insulin-dependent diabetes. Lancet 347: 19–24.Evans SB, Wilkinson CW, Gronbeck P, Bennett JL, Taborsky GJ Jr, Figlewicz DP (2003). Inactivationof the PVN during hypoglycemia partially simulates hypoglycemia-associated autonomic failure.American Journal of Physiology. 284: R57–65.Fanelli C, Pampanelli S, Epifano L, Rambotti AM, Ciofetta M, Moda F et al. (1994). Relative rolesof insulin and hypoglycaemia on induction of neuroendocrine responses to, symptoms of, anddeterioration of cognitive function in hypoglycaemia in male and female humans. Diabetologia 37:797–807.Feldman M, Schiller LR (1983). Disorders of gastrointestinal motility associated with diabetes mellitus.Annals of Internal Medicine 98: 378–84.Gilbert, RM (1984). Caffeine consumption. In: The Methylxanthines Beverages and Foods: Chemistry,Consumption and Health Effects. Spiller GA, ed. Alan R Liss, New York: 235–301.Gin H, Morlat P, Ragnaud JM, Aubertin J (1992). Short-term effect of red wine (consumed duringmeals) on insulin requirement and glucose tolerance in diabetic patients. Diabetes Care 15: 546–8.Gold AE, MacLeod KM, Frier BM (1994). Frequency of severe hypoglycemia in patients with type Idiabetes with impaired awareness of hypoglycemia. Diabetes Care 17: 697–703.Hagstrom-Toft E, Bolinder J, Ungerstedt U, Arner P (1997). A circadian rhythm in lipid mobilizationwhich is altered in IDDM. Diabetologia 40: 1070–8.Hoi-Hansen T, Pedersen-Bjergaard U, Thorsteinsson B (2005). Reproducibility and reliability ofhypoglycaemic episodes recorded with continuous glucose monitoring system (CGMS) in daily life.Diabetic Medicine 7: 858–62.Jones TW, Porter P, Sherwin RS, Davis EA, O’Leary P, Frazer F et al. (1998). Decreased epinephrineresponses to hypoglycemia during sleep. New England Journal of Medicine 338: 1657–62.Kerr D, Macdonald IA, Heller SR, Tattersall RB (1990). Alcohol causes hypoglycaemic unawareness inhealthy volunteers and patients with Type 1 (insulin-dependent) diabetes. Diabetologia 33: 216–21.Kerr D, Sherwin RS, Pavalkis F, Fayad PB, Sikorski L, Rife F et al. (1993). Effect of caffeine onthe recognition of and responses to hypoglycemia in humans. Annals of Internal Medicine 119:799–804.Kerr D, Cheyne EH, Thomas P, Sherwin RS (2007). Influence of acute alcohol ingestion on thehormonal responses to modest hypoglycaemia in patients with Type 1 diabetes. Diabetic Medicine24: 312–16.Kolaczynski JW, Ylikahri R, Harkonen M, Koivisto VA (1988). The acute effect of ethanol oncounterregulatory response and recovery from insulin-induced hypoglycemia. Journal of ClinicalEndocrinology and Metabolism 67: 384–8.Koivisto VA, Tulokas S, Toivonen M, Haapa E, Pelkonen R (1993). Alcohol with a meal has noadverse effects on postprandial glucose homeostasis in diabetic patients. Diabetes Care 16: 1612–4.Landolt HP, Werth E, Borbely AA, Dijk DJ (1995). Caffeine intake (200 mg) in the morning affectshuman sleep and EEG power spectra at night. Brain Research 675: 67–74.Laurienti PJ, Field AS, Burdette JH, Maldjian JA, Yen YF, Moody DM (2003). Relationship betweencaffeine-induced changes in resting cerebral perfusion and blood oxygenation level-dependent signal.American Journal of Neuroradiology 24: 1607–11.MacCuish AC, Munro JF, Duncan LJP (1970). Treatment of hypoglycaemic coma with glucagon,intravenous dextrose, and mannitol infusion in a hundred diabetics. Lancet ii: 946–9.MacCuish AC (1993). Treatment of hypoglycaemia. In: Hypoglycaemia and Diabetes: Clinical andPhysiological Aspects. Frier BM and Fisher M, eds. Edward Arnold, London: 212–21.
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120 MODERATORS, MONITORING AND MANAGEMENTRyder RE, Owens DR, Hayes TM, Ghatei MA, Bloom SR (1990). Unawareness of hypoglycaemia andinadequate hypoglycaemic counterregulation: no causal relation with diabetic autonomic neuropathy.British Medical Journal 301: 783–7.The DCCT Research Group (1991). Epidemiology of severe hypoglycemia in the Diabetes Controland Complications Trial. American Journal of Medicine 90: 450–9.The Diabetes Control and Complications Trial Research Group (1995). Adverse events and theirassociation with treatment regimens in the Diabetes Control and Complications Trial. Diabetes Care18: 1415–27.The Diabetes Control and Complications Trial Research Group (1997). Hypoglycemia in the DiabetesControl and Complications Trial. The Diabetes Control and Complications Trial Research Group.Diabetes 46: 271–86.Ting JW, Lautt WW (2006). The effect of acute, chronic, and prenatal ethanol exposure on insulinsensitivity. Pharmacology and Therapeutics 111: 346–73.Trojan N, Pavan P, Iori E, Vettore M, Marescotti MC, Macdonald IA et al. (1999). Effect of differenttimes of administration of a single ethanol dose on insulin action, insulin secretion and redox state.Diabetic Medicine 16: 400–7.Turner BC, Jenkins E, Kerr D, Sherwin RS, Cavan DA (2001). The effect of evening alcohol consump-tion on next-morning glucose control in type 1 diabetes. Diabetes Care 24: 1888–93.UK Hypoglycaemia Group (2007). Risk of hypoglycaemia in types 1 and 2 diabetes: effects oftreatment modalities and their duration. Diabetologia 50: 1140–7.Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J (1993). Induction of hypoglycemia unawarenessby asymptomatic nocturnal hypoglycemia. Diabetes 42: 1233–7.Vinik AI, Maser RE, Mitchell BD, Freeman R (2003). Diabetic autonomic neuropathy. Diabetes Care26: 1553–79.Ward CM, Stewart AW, Cutfield RG (1990). Hypoglycaemia in insulin dependent diabetic patientsattending an outpatients’ clinic. New Zealand Medical Journal 25: 339–41.Watson JM, Jenkins EJ, Hamilton P, Lunt MJ, Kerr D (2000). Influence of caffeine on the frequencyand perception of hypoglycemia in free-living patients with type 1 diabetes. Diabetes Care 23:455–9.Wehrenberg WB, Janowski BA, Piering AW, Culler F, Jones KL (1990). Glucocorticoids: potentinhibitors and stimulators of growth hormone secretion. Endocrinology 126: 3200–3.Yki-Jarvinen H, Nikkila EA (1985). Ethanol decreases glucose utilisation in healthy man. Journal ofClinical Endocrinology and Metabolism 61: 941–5.
122 COUNTERREGULATORY DEFICIENCIES IN DIABETES–5.00.05.010.015.020.012:00AM4:00AM8:00AM12:00PM4:00PM8:00PM12:00AMGlucose(mmol/L)Figure 6.1 Interstitial glucose values over three days measured by continuous glucose monitoringand showing persistent nocturnal hypoglycaemia0%10%20%30%40%50%RetinopathyKidney disease25 yearsFigure 6.2 Reduction in prevalence of microvascular complications over the past 25 years fromspecialist diabetes centres. Adapted from Rossing (2005), with kind permission from Springer Scienceand Business MediaNORMAL GLUCOSE COUNTERREGULATIONUnder normal circumstances, the brain uses glucose as its predominant fuel and is almostcompletely dependent upon a continuous supply of glucose from the peripheral circulationto maintain normal function. Consequently, to protect the delivery of glucose to the brain,a hierarchy of (counterregulatory) responses (Figure 6.4) are activated as peripheral bloodglucose falls below normal (Mitrakou et al., 1991). The main components of this systemof normal (i.e. non-diabetic) glucose counterregulation, which prevents or quickly correctshypoglycaemia, are as follows:• A reduction in pancreatic -cell insulin secretion.• An increase in pancreatic -cell glucagon secretion. If hypoglycaemia is prolonged anumber of other hormones are also released. These include epinephrine (adrenaline),growth hormone and cortisol.
NORMAL GLUCOSE COUNTERREGULATION 12322A20181614Rate/100Patientyears121086421992 1994 1996Calender Year1998 2000Incidence rate2002Figure 6.3 Rates of severe hypoglycaemia in 1335 children between 1992 and 2002. Hypoglycaemiahas remained problematical despite a fall in HbA1c of 0.2% per year and increased use of multiple dailyinjections, insulin analogues and pump therapy. Adapted from Bulsara et al. (2004) and reproducedcourtesy of The American Diabetes Association• Activation of the autonomic nervous system with the development of characteristicwarning symptoms.• During more profound hypoglycaemia (blood glucose < 2 0mmol/l), glucose delivery tothe brain is enhanced as a consequence of increasing cerebral blood flow (Thomas et al.,1997).• Hepatic autoregulation, whereby the liver is able to respond to hypoglycaemia by directlyincreasing glucose production in the absence of detectable hormonal stimulation. Hepaticautoregulation only appears to have an influential role in glucose counterregulation duringprolonged and severe hypoglycaemia (Tappy et al., 1999).The principal counterregulatory hormones, glucagon and epinephrine, directly increase theproduction of glucose by the liver as a consequence of the breakdown of hepatic glycogenstores (glycogenolysis) and the manufacture of glucose by gluconeogenesis. Epinephrinealso promotes muscle glycogenolysis, proteolysis and lipolysis to provide substrates (lactate,alanine and glycerol) for further gluconeogenesis (Figure 6.5).As blood glucose falls below normal, these hormonal responses are not secreted on an ‘allor nothing’ basis. Individual hormones have specific blood glucose thresholds at which levelsbegin to rise above their baseline levels (Figure 6.6). For example, the glycaemic thresholdsfor the release of glucagon and epinephrine are well above the thresholds for the generationof warning symptoms and impairment of higher brain (cognitive) function (Mitrakou et al.,1991). These thresholds are not fixed but can be altered upwards or downwards according to
124 COUNTERREGULATORY DEFICIENCIES IN DIABETESHypothalamusPituitary glandGrowth hormoneCortisolEpinephrineNorepinephrineGlucagonPancreasAdrenalglandACTHAutonomicNervousSystemFigure 6.4 The brain is the key regulatory organ involved in glucose counterregulationthe prevailing quality of glycaemic control. They do not appear, however, to be influencedby the rate of fall of blood glucose within the hyper- or euglycaemic range.The key organ in coordinating the hormonal and other responses to hypoglycaemia isthe brain. Although numerous neural areas have been proposed as the control centres forcounterregulation, it is likely that neurones located within the ventro-medial nuclei of thehypothalamus are essential for integrating the hormonal responses to a fall in peripheralblood glucose (Borg et al., 1994), possibly via ATP-sensitive K+ channels (McCrimmonet al., 2005), although other glucoreceptors outside the brain are involved in initiating thecounterregulatory responses, most notably within the liver (Smith et al., 2002). Althoughthe brain was once thought to be insensitive to insulin, there is clinical evidence to suggestthat insulin can act on the central nervous system (CNS) to influence the physiologicalresponses to hypoglycaemia (Kerr et al., 1991). Recently, in studies using brain/neuronalinsulin receptor knockout mice (i.e., mice with absent insulin receptor proteins in the brain),the induction of hypoglycaemia was associated with an attenuated epinephrine and an almostcompletely absent norepinephrine response, although glucagon release was unaffected whencompared to control animals. Therefore it appears that insulin has a role in protecting theCNS against hypoglycaemia (Fisher et al., 2005).
NORMAL GLUCOSE COUNTERREGULATION 125Figure 6.5 Principal metabolic effects of counterregulation in response to hypoglycaemiaGlucose (mmol/l)4.03.02.0Release of hormonesWarning symptomsCognitive impairmentIncreased brain blood flowFigure 6.6 Blood glucose thresholds for release of counterregulatory hormones, onset of warningsymptoms of hypoglycaemia and cognitive impairment as blood glucose falls below normal
126 COUNTERREGULATORY DEFICIENCIES IN DIABETESIn type 1 diabetes there may be multiple defects in normal glucose counterregulationwhich significantly increase an individual’s risk of hypoglycaemia. Defects in hormonalcounterregulation can result as a consequence of the following:• secretion of inadequate amounts of counterregulatory hormones;• alteration of the blood glucose threshold at which the hormones are released; i.e., a moreprofound hypoglycaemic stimulus is required before hormonal secretion increases abovebaseline;• diminished tissue sensitivity to a given plasma concentration of hormone.In type 1 diabetes, the most common scenario for increasing the risk of recurrent hypo-glycaemia includes a reduced (but not absent) epinephrine response to falling blood glucoselevels, sustained peripheral hyperinsulinaemia and an absent glucagon response – this constel-lation of defects is associated with a 25-fold increased risk of severe hypoglycaemia inpeople who are on intensive insulin therapy. If impaired hypoglycaemia awareness is present,the risk is increased six fold (see Chapter 7).DEFECTIVE HORMONAL GLUCOSE COUNTERREGULATIONThe most important defects in glucose counterregulation in type 1 diabetes are:• failure of circulating plasma insulin levels to decline (i.e., as a consequence of exogenousinsulin administration);• failure of glucagon secretion from pancreatic -cells;• attenuated epinephrine response to hypoglycaemia.Several factors are known to increase the risk of counterregulatory failure, including:• long duration of diabetes;• extremes of age;• improving glycaemic control;• sleep;• exercise;• recurrent hypoglycaemia – related to the degree rather than duration of antecedent hypo-glycaemia (Davis et al., 2000a).The defects in glucose counterregulation are not ‘all or nothing’ and are influenced by anumber of factors. Some of the defects may be reversible.
DEFECTIVE HORMONAL GLUCOSE COUNTERREGULATION 127GlucagonIn non-diabetic individuals, glucagon is secreted by pancreatic -cells within 30 minutes ofthe blood glucose falling below normal. It is released directly as a consequence of local tissueglucopenia and indirectly by sympathetic neural inputs to the pancreas. It is unclear whetherlocal (pancreatic) tissue glucopenia or autonomic activation is the key process involved instimulating the release of glucagon during hypoglycaemia.In people with type 1 diabetes, the glucagon secretory response to hypoglycaemia isinitially diminished and is subsequently lost within a few years of the onset of diabetes(Gerich et al., 1973), although it can be released in response to other stimuli, such as exerciseor an intravenous infusion of arginine (Gerich and Bolli, 1993). This indicates that the failureof the glucagon response is most probably a signalling rather than a structural defect. Loss ofthe glucagon response to hypoglycaemia often coexists with clinical evidence of autonomicneuropathy but the latter is not invariably present (Bolli et al. 1983). Although recent studieshave suggested that an early sympathetic neuropathy limited to the pancreatic islets may bea potential mechanism, patients with pancreatic transplants (i.e., denervated islets) can stillproduce glucagon in response to hypoglycaemia (Diem et al., 1990). The cause of the defectin glucose counterregulation is not known but may include:• reduction in pancreatic -cell mass;• autonomic neuropathy;• local effect of insulin on normal -cell function;• generalised hyperinsulinaemia;• chronic hyperglycaemia;• increased pancreatic production of somatostatin;• accumulation of amylin within the islets;• local effect of insulin-like growth factor-1.An alternative hypothesis to explain the glucagon-counterregulatory defect suggests thatin healthy individuals a decrease in intra-islet insulin in association with a decrease in-cell glucose is the usual signal for release of glucagon as peripheral blood glucose levelsfall (Samols et al., 1972). Support for this comes from the observation that infusion ofthe -cell secretagogue, tolbutamide, prevents the glucagon response to hypoglycaemia innon-diabetic individuals (Banarer and Cryer, 2003). Similarly, supraphysiological levels ofinsulin have been shown to impair glucagon release in response to moderate hypoglycaemia(Kerr et al., 1991). Blunting of the normal glucagon response to hypoglycaemia can alsobe achieved in healthy volunteers by infusion of insulin-like growth factor-1 (IGF-1), theputative mediator of the somatotrophic action of growth hormone, at least in non-diabetichumans (Kerr et al., 1993) (Figure 6.7). Whether IGF-1 is involved in the pathogenesis ofglucagon counterregulatory failure in patients with type 1 diabetes is unclear.Alternatively, it is possible that chronic hyperglycaemia may directly impair pancreatic-cell function through the mechanism of glucose toxicity similar to the effect that this has on-cell function. Nevertheless, improvements in glycaemic control, following introduction of
128 COUNTERREGULATORY DEFICIENCIES IN DIABETESFigure 6.7 Infusion of insulin-like growth factor 1 abolishes the expected rise in glucagon whenblood glucose was lowered to, and maintained at, 2.8 mmol/l in healthy volunteers. Reproduced fromKerr et al. (1993) by permission of The Journal of Clinical Investigationintensive insulin therapy, invariably fail to restore the glucagon responses to hypoglycaemia(Amiel, 1991). The early appearance of an impaired response of glucagon, together with atemporal dissociation from deficiencies in other counterregulatory hormones, argues againstthis abnormality being mediated from within the central nervous system.Impairment of the glucagon response to hypoglycaemia results in greater suppressionof hepatic glucose production by insulin. Since the ability of insulin to increase glucoseutilisation is unaltered, glucose uptake by muscle and other tissues will exceed hepaticglucose production for much longer, resulting in more profound and prolonged hypogly-caemia. Whether or not the lack of a glucagon response is by itself sufficient to increase thefrequency of severe hypoglycaemia is unclear; most patients with recurrent severe hypogly-caemia have impairment both of glucagon and epinephrine release.CatecholaminesAn attenuated epinephrine response (from the adrenal medulla) to falling blood glucoselevels together with an absent glucagon response markedly increases the risk of severehypoglycaemia in individuals with type 1 diabetes. It is unknown how common epinephrinecounterregulatory failure is in type 1 diabetes, but it is related to the duration of diabetesand the prevailing quality of glycaemic control. Estimates suggest this defect may exist inup to 45% of people with type 1 diabetes of long duration (Gerich and Bolli, 1993).The epinephrine response to hypoglycaemia can be subnormal in patients with type 1diabetes who have no clinical evidence of autonomic neuropathy and also in individualswith secondary (pancreatic) diabetes. Like glucagon, the epinephrine secretory deficiency isstimulus-specific to hypoglycaemia, remaining intact in response to exercise. The isolated
DEFECTIVE HORMONAL GLUCOSE COUNTERREGULATION 129failure of plasma epinephrine concentrations to rise in response to hypoglycaemia doesnot appreciably impair glucose counterregulation – unless it is combined with glucagondeficiency (as occurs in patients with long-standing type 1 diabetes), when the risk of severeand prolonged hypoglycaemia is significantly increased.As mentioned above, deficient sympathoadrenal responses to hypoglycaemia are majorcomponents of the clinical problem of defective glucose counterregulation and impairedawareness of hypoglycaemia in type 1 diabetes (Cryer, 2004; 2005). This may occur as aresult of the following:• reduced release of catecholamines and acetyl choline;• possibly a reduction in tissue sensitivity to the actions of these substances, although thisis controversial.Of clinical importance is the observation that a hypoglycaemic episode per se, adverselyalters the subsequent sympathoadrenal responses to hypoglycaemia (Heller and Cryer, 1991).Cryer has termed this Hypoglycaemia Associated Autonomic Failure (HAAF) (Figure 6.8).In other words, a recent episode of hypoglycaemia, known as ‘antecedent hypoglycaemia’,(including an asymptomatic event) diminishes the sympathoadrenal, symptomatic and cogni-tive responses to subsequent hypoglycaemia. As a corollary, avoidance of hypoglycaemia(for as little as two weeks) markedly improves the responses (Cranston et al., 1994). Sympa-thoadrenal responses to hypoglycaemia are also affected by recent exercise, whether the fallin blood glucose level occurs when an individual is awake or asleep (Jones et al., 1998;Banarer and Cryer, 2003) (Figure 6.9) and by the time of day or night (Merl et al., 2004).Insulin Deficient Diabetes(Imperfect Insulin Replacement)(No Insulin, No Glucagon)Antecedent HypoglycaemiaSleepReduced SympathoadrenalResponses to HypoglycaemiaReduced SympatheticNeural ResponsesHypoglycaemiaUnawarenessRecurrent HypoglycaemiaDefective GlucoseCounterregulationReduced EpinephrineResponsesAntecedentExerciseFigure 6.8 Hypoglycaemia Associated Autonomic Failure (HAAF) in type 1 diabetes. Adapted fromCryer (2005) and reproduced courtesy of The American Diabetes Association
130 COUNTERREGULATORY DEFICIENCIES IN DIABETESMorning awakeAsleepNight awakeNominal glucose (mg/dl)85(a)Epinephrine(pg/ml)pmol/l6005004003002001000300025002000150010005000Time (min)0 60 120 180 240 30075 65 55 45Nominal glucose (mg/dl)85(b)Epinephrine(pg/ml)pmol/l6005004003002001000300025002000150010005000Time (min)0 60 120 180 240 30075 65 55 45Figure 6.9 Plasma epinephrine (adrenaline) in non-diabetic subjects (a) and in patients with type 1diabetes (b) studied in the morning while awake and during the night while awake and asleep. Adaptedfrom Banarer and Cryer (2003) and reproduced courtesy of The American Diabetes Association( morning awake; • night awake; asleep)Cortisol and Growth HormoneGrowth hormone (GH) and cortisol are thought to become important glucose-raisinghormones only after hypoglycaemia has been prolonged for more than one hour. However,defects in cortisol and GH release can cause profound and prolonged hypoglycaemia becauseof a reduction in hepatic glucose production and, to a lesser extent, by exaggeration ofinsulin-stimulated glucose uptake by muscle.Abnormalities in growth hormone and cortisol secretion in response to hypoglycaemiaare characteristic of long-standing type 1 diabetes, affecting up to a quarter of patientswho have had diabetes for more than ten years. In rare cases, coexistent endocrine failuresuch as Addison’s disease or hypopituitarism also predisposes patients to severe hypogly-caemia. Pituitary failure, although uncommonly associated with type 1 diabetes, occasionallydevelops in young women as a consequence of ante-partum pituitary infarction. As anintact hypothalamic–pituitary–adrenal axis is important for adequate counterregulation, thisaxis should be formally assessed in any individual with brittle diabetes presenting withunexplained, recurrent hypoglycaemia (Hardy et al., 1994; Flanagan and Kerr, 1996).More commonly, ingestion of even modest amounts of alcohol can significantly attenuatenormal growth hormone secretion and increase the risk of hypoglycaemia especially thefollowing morning (see Chapter 5).MECHANISMS OF COUNTERREGULATORY FAILUREAt the onset of type 1 diabetes, hormonal counterregulation is usually normal but within fiveyears of diagnosis, glucagon responses to hypoglycaemia become markedly impaired or evenabsent, although a glucagon response can occur if the hypoglycaemic stimulus is sufficientlyprofound (Frier et al. 1988; Hvidberg et al. 1998). After ten years of diabetes, patients usuallyhave a sub-optimal epinephrine response to compound the absent glucagon response to a fall
132 COUNTERREGULATORY DEFICIENCIES IN DIABETESSystemic MediatorThe systemic mediator theory suggests that a substance is released in response to hypogly-caemia which attenuates subsequent sympathoadrenal responses to further episodes of hypo-glycaemia. The initial candidate for this was cortisol, based on two observations: first, theattenuating effect of antecedent hypoglycaemia on later sympathoadrenal responses is absentin patients with primary adrenocortical failure; and second, in healthy volunteers, followinginfusions of cortisol (to supraphysiological levels) during euglycaemia, adrenomedullaryepinephrine secretion and muscle sympathetic neural activity were reduced during subse-quent hypoglycaemia (Davis et al., 1996; 1997). However, this effect of cortisol is lost ifthe prevailing cortisol levels are lowered towards those seen during hypoglycaemia or ifrecurrent hypoglycaemia is induced in animals that are genetically modified to have absentadrenocortical responses (Raju et al., 2003; McGuiness et al., 2005).Brain Fuel TransportThis mechanism is based on the hypothesis that following antecedent hypoglycaemia, glucosetransport from blood into brain tissue is increased – in animals by increasing GLUT-1 transportacross the brain microvasculature (McCall et al., 1986; Kumagai et al., 1995). In patients withtype 1 diabetes whose treatment resulted in near normal glucose levels, impaired awareness ofhypoglycaemia can develop – such patients are at increased risk of seizures and coma. Boyleet al. (1995) tested the hypothesis that during hypoglycaemia, these patients would have normalglucose uptake in the brain and consequently that sympathoadrenal activation would not occur,resulting in impaired awareness of hypoglycaemia. They found that there was no significantchange in the uptake of glucose in the brain among the patients with type 1 diabetes who hadthe lowest HbA1c levels. Conversely, glucose uptake in the brain fell in patients with less well-controlled type 1 diabetes. The responses of plasma epinephrine and pancreatic polypeptide andthe frequency of symptoms of hypoglycaemia were also lowest in the group with the lowestHbA1c values. They concluded that during hypoglycaemia, patients with nearly normal HbA1cvalues have normal glucose uptake in the brain, preserving cerebral metabolism, reducing theresponses of counterregulatory hormones, and causing impaired awareness of hypoglycaemia(Boyle et al., 1995). However, these findings occurred after days of prolonged hypoglycaemiawhich is in contrast to the clinical observation that attenuated sympathoadrenal responses occurwithin hours of a hypoglycaemic event.More recently, studies using positron emission tomography have found no change in blood-to-brain glucose transport 24 hours after an episode of hypoglycaemia and no differencesbetween individuals with and without hypoglycaemia awareness (Segel et al., 2001; Binghamet al., 2005). It remains possible, however, that there are changes in the transport of alternativecerebral fuels following antecedent hypoglycaemia.Brain MetabolismIt has been hypothesised that brain metabolism per se is altered following an episode ofhypoglycaemia. Most research in this area has focused on the ventromedial nucleus of thehypothalamus. Glucose deprivation in the VMH (by administration of 2-deoxyglucose) acti-vates the sympathoadrenal system and increases glucagon secretion whereas local perfusion
AGE, OBESITY AND GLUCOSE COUNTERREGULATION 133AdenosineDeliveryUtilisationGlucoseCaffeineFigure 6.11 Caffeine may act by uncoupling brain glucose demand (increased) and substrate delivery(decreased) through its actions on adenosine receptors. Reproduced from Brain Research Reviews, 17,Nehlig et al., 139–169, Copyright (1992), with permission from Elsevierof the area with glucose suppresses these responses during systemic hypoglycaemia (Borget al., 1995; Borg et al., 1997). The mechanisms involved are unknown but may be a conse-quence of increased glucokinase activity to enhance glucose metabolism in neurones in theregion (Gabriely and Shamoon, 2005). However, it is likely that brain metabolism in areasand other signalling mechanisms within the CNS are influenced by recurrent antecedenthypoglycaemia (Cryer, 2005).The brain glycogen supercompensation hypothesis suggests that after a single episodeof hypoglycaemia, there is a rebound increase in glycogen formation in brain astrocytes toprovide additional substrates (e.g. lactate) for brain metabolism (Choi et al., 2003). Alter-ations of substrate delivery to the brain do appear to influence the magnitude of the hormonalcounterregulatory response to hypoglycaemia in healthy volunteers and in patients with type1 diabetes. Infusions of acetazolamide, a potent cerebral vasodilator, markedly attenuatesthese responses (Thomas et al., 1997) whereas ingestion of modest amounts of caffeine (toreduce substrate delivery) augments the responses (Debrah et al., 1996). The mechanismsof the latter is unknown but may involve antagonism of central adenosine receptors withuncoupling of brain blood flow (i.e., substrate delivery) and brain glucose metabolism (i.e.,brain glucose demand) resulting in relative cerebral neuroglycopenia (Figure 6.11). This isdiscussed in more detail in Chapter 5.AGE, OBESITY AND GLUCOSE COUNTERREGULATIONIn children with type 1 diabetes, the glucagon response to hypoglycaemia is markedly attenu-ated compared to non-diabetic individuals but compensated for by vigorous secretion of othercounterregulatory hormones, particularly epinephrine, with the peak epinephrine responsesbeing almost two-fold higher than in adults (Amiel et al., 1987). The total sympathoad-renal responses to hypoglycaemia are also influenced by pubertal stage (Ross et al., 2005).
134 COUNTERREGULATORY DEFICIENCIES IN DIABETESFurthermore, it appears that the glycaemic thresholds for the secretion of epinephrine andgrowth hormone are set at a higher blood glucose level in non-diabetic children comparedto adults (Jones et al., 1991). In children with type 1 diabetes, the secretion of epinephrinein response to hypoglycaemia commences at an even higher level. In children who havemarkedly elevated HbA1c values, there is a further shift of the blood glucose threshold to ahigher level for the release of counterregulatory hormones.Advanced age, in otherwise healthy people, does not appear to diminish or delay coun-terregulatory responses to hypoglycaemia (Brierley et al., 1995), although the magnitudeof responses of epinephrine and glucagon is lower at milder hypoglycaemic levels (around3.4 mmol/l ) compared to younger non-diabetic subjects, but is much more comparablewith a more profound hypoglycaemic stimulus (2.8 mmol/l) (Ortiz-Alonso et al., 1994) (SeeChapter 11). The magnitude of counterregulatory responses to low blood glucose levelsfollowing preceding hypoglycaemia also appears to depend on the gender of experimentalsubjects, with men having blunted responses compared to women (Davis et al., 2000b).Both the autonomic nervous system and the hypothalamic–pituitary–adrenal axis areactivated in excess in the morbidly obese. Before and after bariatric surgery (averageweight loss 40 kg over 12 months), severely obese non-diabetic subjects, underwenta hyperinsulinaemic hypoglycaemic clamp (blood glucose 3.4 mmol/l). Before weightreduction, patients demonstrated brisk peak responses in glucagon, epinephrine, pancre-atic polypeptide, and norepinephrine. After surgery and during hypoglycaemia, all theseresponses were attenuated and most markedly so for glucagon, which was totally abol-ished in association with a marked improvement in insulin sensitivity. In contrast,the growth hormone response was increased after weight reduction (Guldstrand et al.,2003).HUMAN INSULIN AND COUNTERREGULATIONAt present there is no consistent evidence that the species of insulin is an important determi-nant of the counterregulatory response to hypoglycaemia. Over 25 clinical laboratory studieshave examined the effect of insulin species on the counterregulatory response to hypogly-caemia induced by an intravenous bolus, intravenous infusion, or subcutaneous injection ofinsulin (Fisher and Frier, 1993; Jorgensson et al., 1994). Most of the studies showed nosignificant differences between the hormonal responses. Two studies showed a reduction inthe epinephrine response to hypoglycaemia, and both of these studies also reported dimin-ished autonomic symptoms to hypoglycaemia after human insulin (Schluter et al., 1982;Heine et al., 1989).A meta-analysis comparison of the effects of human and animal insulin as well as ofthe adverse reaction profiles did not show clinically relevant differences between speciesespecially in terms of risk and responses to hypoglycaemia (Richter and Neises, 2005).TREATMENT OF COUNTERREGULATORY FAILUREAt present no treatment is available that will reverse the glucagon deficit that developswithin a few years of the onset of type 1 diabetes (Figure 6.12). However, there are strategies
TREATMENT OF COUNTERREGULATORY FAILURE 135TimeTimeTimeGlucagonGlucagonEpinephrineEpinephrineGlucagon andEpinephrineGlucagon andEpinephrineGlucoseGlucoseGlucoseFigure 6.12 Schematic representation of the consequences of defective glucagon, epinephrine or acombined defect of glucagon and epinephrine release during recovery from hypoglycaemiato reduce the risk of hypoglycaemia from causing further hypoglycaemia and promotingHypoglycaemia Associated Autonomic Failure:• relaxation of glycaemic targets;• use of multiple daily injections of insulin, utilising rapid-acting and basal analogues (Bolli,2006);• consideration of switching to continuous subcutaneous insulin infusion therapy (Chaseet al., 2006);
136 COUNTERREGULATORY DEFICIENCIES IN DIABETES• intensive education including carbohydrate counting and appropriate blood glucose moni-toring;• use of novel technologies to aid diagnosis, e.g. continuous glucose monitoring (Cheyneand Kerr, 2002);• discussion of patient factors, e.g. lipohypertrophy and other injection site problems,alcohol, caffeine consumption.Common psychological problems known to affect diabetes management adversely, such asanxiety, depression and eating disorders, have been extensively reported (Jacqueminet et al.,2005). Of particular relevance is the recognition of the role played by high levels of anxiety.Evidence-based treatment interventions are available for treating anxiety in the non-diabeticpopulation; however a systematic review and meta-analysis of randomised controlled trialsof psychological interventions for adults with diabetes has yet to be conducted. In clinicalpractice it continues to be recognised that there is a group of patients whose lives arecompletely disrupted by recurrent episodes of hyper and hypoglycaemia – the so-called‘brittle diabetic’. The outlook for such patients is usually poor (Tattersall et al., 1991).CONCLUSIONS• In non-diabetic individuals, clinically significant hypoglycaemia is an extremely rare eventbecause of effective glucose counterregulation. This includes suppression of endogenouspancreatic insulin secretion, and release of glucagon, catecholamines, cortisol and growthhormone.• The brain is the critical organ for co-ordination of the physiological responses to lowblood glucose levels.• People with diabetes almost inevitably lose their ability to release glucagon in responseto a fall in blood glucose, within five years of diagnosis. After ten years, a significantproportion of patients also has deficient epinephrine responses and is at increased risk ofmore protracted hypoglycaemia and neuroglycopenia.• Modern treatment of type 1 diabetes, including intensive education and treatment regimensutilising new technologies, has failed to eradicate completely the problem of recurrenthypoglycaemia.REFERENCESAmiel SA, Simonson DC, Sherwin RS, Lauriano AA, Tamborlane WV (1987). Exaggeratedepinephrine responses to hypoglycemia in normal and insulin-dependent diabetic children. Journalof Pediatrics 110: 832–7.Amiel S (1991). Glucose counter-regulation in health and disease: current concepts in hypoglycaemiarecognition and response. Quarterly Journal of Medicine 293: 707–27.Banarer S, Cryer PE (2003). Sleep-related hypoglycemia-associated autonomic failure in type 1diabetes: reduced awakening from sleep during hypoglycemia. Diabetes 52: 1195–203.
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140 COUNTERREGULATORY DEFICIENCIES IN DIABETESWeintrob N, Schechter A, Benzaquen H, Shalitin S, Lilos P, Galatzer A, Phillip M (2004). Glycemicpatterns detected by continuous subcutaneous glucose sensing in children and adolescents withtype 1 diabetes mellitus treated by multiple daily injections versus continuous subcutaneous insulininfusion. Archives of Pediatric and Adolescent Medicine 158: 677–84.White NH, Gingerich RL, Levandoski LA, Cryer PE, Santiago JV (1985). Plasma pancreatic polypep-tide response to insulin-induced hypoglycemia as a marker for defective glucose counterregulationin insulin-dependent diabetes. Diabetes 34: 870–5.
142 IMPAIRED AWARENESS OF HYPOGLYCAEMIAArterialisedvenousbloodglucoseconcentration(mmol/L)5.04.03.02.01.00Inhibition of endogenousinsulin secretion4.6 mmol/LOnset of symptoms3.2–2.8 mmol/LCognitivedysfunction2.8 mmol/LCounterregulatoryhormone releaseNeurophysiologicaldysfunction3.0–2.4 mmol/L< 1.5 mmol/LSevereneuroglycopeniaWidespreadEEG changes3.0 mmol/L3.8 mmol/L• Evoked responses• Reducedconscious level• Convulsions• Coma• Autonomic• Neuroglycopenic• Glucagon• Epinephrine• Inability toperform complextasksFigure 7.1 Hierarchy of endocrine, symptomatic and neurological responses to acute hypoglycaemiain non-diabetic subjects. Glycaemic thresholds are based on glucose concentrations in arterialisedvenous blood. Modified from Textbook of Diabetes, 2nd edition (1997) (eds J. Pickup and G. Williams),by permission of Blackwell Science LtdDepriving the brain of glucose causes it to malfunction, and cognitive impairment quicklybecomes evident as an overt manifestation of neuroglycopenia. Some of these features arerelatively subtle, and may not be detected immediately by the patient. A fall in blood glucosetriggers activation of the peripheral autonomic nervous system via central hypothalamic auto-nomic centres within the brain, and stimulates the sympathoadrenal system. This promotestypical physiological responses including sweating, an increase in rate and contractility of theheart (sensed as a pounding heart), and tremor, these being some of the classical features ofthe autonomic reaction (Figure 7.2). Epinephrine (adrenaline) is secreted in large quantitiesfrom the adrenal medullae and contributes to some of the symptoms mainly by heighteningthe magnitude of the response. The early literature on hypoglycaemia and diabetes providesaccurate descriptions of the autonomic features of acute hypoglycaemia, and patients andphysicians alike commonly discussed hypoglycaemic ‘reactions’, a term that regrettably isnow seldom used. It emphatically describes the sudden, and often florid, onset of the auto-nomic features of hypoglycaemia, which drive the individual to seek assistance or obtain asupply of glucose to relieve these unpleasant symptoms.‘Awareness’ of HypoglycaemiaThe generation of typical physiological responses to hypoglycaemia is perceived throughsensory feedback to the brain, and after central processing, an appropriate motor responseis made. Much has been made by some commentators of the predominant importanceof autonomic symptoms in the detection of the onset of hypoglycaemia. This premise is
144 IMPAIRED AWARENESS OF HYPOGLYCAEMIAneuroglycopenia, but most patients detect (and often rely upon) neuroglycopenic symptomsduring early hypoglycaemia, and rate these as important as autonomic symptoms in providinga warning. It is the initial perception of any symptom of hypoglycaemia, irrespective ofwhether this is autonomic, neuroglycopenic or simply a vague sensation of apprehension orloss of well-being (a common early feature described by many) which constitutes ‘awareness’of hypoglycaemia. Only the initial warning symptoms are important in this respect, and notthe total spectrum or absolute number of symptoms, some of which occur too late to haveany value in alerting the patient to the impending risk of a falling blood glucose. A majordifference between the autonomic and the neuroglycopenic symptomatic response is that,once triggered, the autonomic response quickly reaches a maximum intensity which thengradually declines with time, whereas the neuroglycopenic response becomes more profoundthe further the blood glucose falls. This qualitative difference in response becomes importantif early cues are ignored or are not detected, as progressive neuroglycopenia will eventuallyinterfere with the individual’s ability to identify and self-treat the low blood glucose.When a person is fully awake, alert and on guard against possible hypoglycaemia, this symp-tomatic warning system generally works very effectively (Chapter 2). However, there are manytimes in everyday life when the symptoms may be either diminished or disregarded. This isparticularly so during sleep when symptoms are seldom detected, or they may be ignoredif a person is distracted by other activities, such as watching an interesting programme ontelevision, participating in sport or concentrating on a task. Circumstances can modify thevalue of specific warning symptoms, making them difficult to interpret as features of hypo-glycaemia. Examples include sweating on a hot day, shivering when the weather is cold orfeeling drowsy during a boring meeting! All of these may represent early hypoglycaemiabut are attributed to other causes by the affected person. A list of the factors that influencenormal awareness of hypoglycaemia is shown in Box 7.1. The intensity of symptoms canvary and the value of individual symptoms as warning features may not be constant in anysingle individual. This is often not appreciated in the assessment of research findings, and it isdifficult to extrapolate the careful measurement of symptomatic responses to hypoglycaemiain studies performed in a laboratory setting, to the hurly-burly of everyday life.Box 7.1 Factors influencing normal awareness of hypoglycaemiaInternal ExternalPhysiological DrugsRecent glycaemic control Beta-adrenoceptor blockers (non-selective)Degree of neuroglycopenia Hypnotics, tranquillisersSymptom intensity/sensitivity AlcoholPsychological EnvironmentalFocused attention PostureCongruence; denial DistractionCompeting explanationsEducationKnowledgeSymptom belief
IMPAIRED AWARENESS OF HYPOGLYCAEMIA 145Warning symptoms provide internal cues, but most people with insulin-treated diabetesalso rely on external cues based on their experience of the timing of insulin administrationin relation to food, the effect of delaying meals or the amount of food ingested, the effect ofexercise on blood glucose and many other factors that can influence short-term glycaemiccontrol. These cues are supplemented by blood glucose monitoring, which gives an exactand objective measure of prevailing glycaemia. Further useful feedback may be obtainedfrom observers such as relatives or friends, many of whom become adept at noticing earlyneuroglycopenia before the onset of the patient’s subjective warning symptoms. ‘Awareness’of hypoglycaemia is therefore distilled from a combination of resources, and has to belearned by people with newly diagnosed diabetes commencing insulin therapy. They have noprevious experience of symptoms of hypoglycaemia and must receive appropriate educationon the potential range of symptoms. Through experience they will recognise the clusterof symptoms peculiar to themselves, because symptoms are idiosyncratic. Awareness ofhypoglycaemia therefore assists in protecting the individual from the risk of an unexpectedfall in blood glucose. When awareness of hypoglycaemia becomes impaired or is absentwhile a person is awake, the individual becomes progressively vulnerable to the developmentof severe hypoglycaemia.IMPAIRED AWARENESS OF HYPOGLYCAEMIADefinitionNo satisfactory or comprehensive definition of impaired hypoglycaemia awareness has beensuggested to date. Many laboratory-based studies of experimental hypoglycaemia have usedarbitrary definitions based on witnessed observations of subjects who fail to develop clas-sical features of hypoglycaemia, or the failure of physiological or hormonal responses toexceed twice the standard deviation from mean basal levels. These are statistical devices,which take no account of subjective reality, require the application of sophisticated andunphysiological glucose clamp procedures, and have little direct application to clinicalmanagement.Asymptomatic biochemical hypoglycaemia occurs more frequently during routine bloodglucose monitoring in diabetic patients who report impaired awareness of hypoglycaemia(Gold et al., 1994; Clarke et al., 1995) and such a record may alert the clinician to thepossibility that an individual is developing this problem. A much higher rate of undetectedhypoglycaemia in people with impaired awareness has been demonstrated during wakinghours using continuous blood glucose monitoring (Kubiak et al., 2004). However, in clinicalpractice a careful history is essential in determining whether reduced warning symptoms ofhypoglycaemia are a significant problem, and if this is occurring consistently. Patients whoassert that they have a problem with perceiving the onset of symptoms of hypoglycaemiaare generally correct in this belief (Clarke et al., 1995), so that the identification of impairedawareness of hypoglycaemia should be based principally on clinical history. Validatedscoring systems to assess awareness of hypoglycaemia have been described by Gold et al.(1994) and Clarke et al. (1995), and supportive information can be derived from simultaneousinspection of the individual’s blood glucose results. Detailed questioning of a patient about hisor her ability to detect the onset of hypoglycaemic symptoms may need to be supplementedby questioning close relatives, who often report a much higher rate of severe hypoglycaemia
146 IMPAIRED AWARENESS OF HYPOGLYCAEMIA(Heller et al., 1995; Jorgensen et al., 2003). This will provide a witnessed descriptionof how hypoglycaemia develops in a patient, with information on its true frequency andseverity. Patients often underestimate the frequency of severe hypoglycaemia, partly becauseof post-hypoglycaemia amnesia.ClassificationIn one study, Hepburn et al. (1990) subdivided hypoglycaemia awareness into three cate-gories: normal, partial and absent awareness. These were defined as follows:• Normal awareness: the individual is always aware of the onset of hypoglycaemia.• Partial awareness: the symptom profile has changed with a reduction either in the intensityor in the number of symptoms and, in addition, the individual may be aware of someepisodes of some episodes of hypoglycaemia but not of others.• Absent awareness: the individual is no longer aware of any episode of hypoglycaemia.Although the subdivision into partial and absent awareness is artificial, it reflects the naturalhistory of this clinical problem, illustrating the gradual progression of this disability, andemphasising that in some patients the abnormality is severe (absent awareness) althoughtotal absence of clinical manifestations of hypoglycaemia (particularly the neuroglycopenicfeatures) is exceptionally rare (Gold et al., 1994, Clarke et al., 1995). The problem maynot be simply an absence of symptoms, but rather that the time during which warningsymptoms can be detected is extremely short, allowing the affected individual a very limitedopportunity to take avoiding action. Some patients describe how the onset of hypoglycaemiaappears to have become much more rapid compared with their previous experience andprogresses quickly to severe neuroglycopenia. However, impaired awareness may not neces-sarily evolve into total unawareness of hypoglycaemia, and may vary over time, presumablybecause of major influences of environmental factors on the generation and perception ofsymptoms.The above classification of awareness of hypoglycaemia is far from comprehensive. Inaddition, the state of hypoglycaemia awareness can be ascertained only when the individualis in a physical state in which recognition of the onset of hypoglycaemia is possible.Therefore, if the person is asleep, intoxicated, inebriated, anaesthetised or sedated, so thattheir conscious level is reduced, they are not able to perceive (as subjective symptoms)the normal physiological manifestations of hypoglycaemia. An individual’s awareness ofhypoglycaemia can be evaluated only if hypoglycaemia occurs while the individual is awake.A further prerequisite is that the person must have had previous experience of hypo-glycaemia at some time during treatment with insulin. In assessing the present state ofhypoglycaemia awareness, it is desirable that the patient should have experienced one ormore episodes of hypoglycaemia (confirmed biochemically) within a recent time intervalsuch as the preceding year, so that a comparison of the symptoms can be made with earlierepisodes of hypoglycaemia. A diagnosis of impaired hypoglycaemia awareness cannot beentertained or surmised if a patient has either never been exposed previously to acute hypo-glycaemia or has only started to experience hypoglycaemic events very recently. Becausehypoglycaemia awareness and its impairment is a continuum ranging from normality to
PREVALENCE OF IMPAIRED AWARENESS OF HYPOGLYCAEMIA 147complete inability to detect the onset of hypoglycaemia, a classification of this conditionwill need to consider alterations in symptom intensity as well as detection of hypoglycaemiaby any means and the ability of the patient to self-treat low blood glucose.PREVALENCE OF IMPAIRED AWARENESS OFHYPOGLYCAEMIAImpaired awareness of hypoglycaemia is common in people treated with insulin. Althoughthe chronic form of this acquired condition mainly affects those with type 1 diabetes, itappears that a similar problem does eventually emerge in patients with type 2 diabetes whohave been treated with insulin for several years (Hepburn et al., 1993a). A prevalence of 8%was observed in a cohort of 215 patients in Edinburgh (Henderson et al., 2003). Becausefew patients with type 2 diabetes who require insulin therapy survive for a sufficientlylong period to permit this complication to develop, impaired awareness is principally aproblem associated with type 1 diabetes. It is not known whether impaired awareness ofhypoglycaemia occurs in diabetic patients treated with oral antidiabetic agents.Impaired awareness of hypoglycaemia has been shown to be associated with strictglycaemic control (see Chapter 8), but significant modification of the symptomatic responseto hypoglycaemia does not occur unless the glycated haemoglobin concentration is withinthe non-diabetic range (Boyle et al., 1995; Kinsley et al., 1995; Pampanelli et al., 1996).Only a small proportion of people with insulin-treated diabetes can sustain this degree ofsuper-optimal glycaemic control indefinitely. In the Diabetes Control and ComplicationsTrial (DCCT), with its extensive resources devoted to maintaining intensive insulin therapy,more than 40% of the patients in the group with strict glycaemic control achieved a HbA1c of6.05% or less (the upper limit of the non-diabetic range) at some time during the study, butonly 5% were able to maintain this level of glycaemic control continuously (The DiabetesControl and Complications Trial Research Group, 1993). The proportion of any insulin-treated diabetic population that can achieve this therapeutic goal will depend on local policiesregarding insulin therapy, the expertise of local diabetes specialist teams, available resourcesand the enthusiasm of individual patients. With the exception of a few highly motivatedpatients, most people treated with insulin are unable to maintain strict glycaemic controlfor protracted periods. In clinical practice this ‘acute’ form of hypoglycaemia unawarenessis probably relatively uncommon. Nonetheless, the influence of strict glycaemic control onsymptomatic and counterregulatory responses to hypoglycaemia has been studied exten-sively, and has provided insights into the potential pathogenetic mechanisms underlyingimpaired awareness of hypoglycaemia.Reduced warning symptoms of hypoglycaemia (of varying severity) occur in approx-imately one quarter of all insulin-treated patients. Cross-sectional population surveys indifferent European and North American populations of insulin-treated diabetic patients, usingsimilar methods of assessment, have given remarkably consistent estimates (Table 7.1).Impaired awareness of hypoglycaemia becomes more common with increasing duration ofinsulin-treated diabetes (Hepburn et al., 1990), and almost 50% of patients experience hypo-glycaemia without warning symptoms after 25 years or more of treatment (Pramming et al.,1991) (Figure 7.3). It appears therefore to be an acquired abnormality associated with insulintherapy.
148 IMPAIRED AWARENESS OF HYPOGLYCAEMIATable 7.1 Prevalence of Hypoglycaemia Unawareness in population studies ofinsulin-treated diabetesCountryNumber ofpatientsImpaired awareness ofhypoglycaemia (%) ReferenceScotland 302 23 Hepburn et al. (1990)Germany 523 25 Muhlhauser et al. (1991)Denmark 411 27 Pramming et al. (1991)USA 628 20 Orchard et al. (1991)Figure 7.3 Comparisons between the duration of diabetes and the percentage of 411 type 1 diabeticpatients reporting (a) changes in symptoms of hypoglycaemia, (b) sweating and/or tremor as one of thetwo cardinal autonomic symptoms of hypoglycaemia, and (c) severe hypoglycaemic episodes withoutwarning symptoms. Values are medians; shaded areas show 95% confidence limits. Reproduced fromPramming et al. (1991) by permission of John Wiley & Sons, Ltd
PATHOGENESIS OF IMPAIRED AWARENESS OF HYPOGLYCAEMIA 149Frequency of Associated Severe HypoglycaemiaIt is apparent that impaired awareness of hypoglycaemia is a major risk factor for severehypoglycaemia. In the DCCT, 36% of all episodes of severe hypoglycaemia occurred withno warning symptoms in patients while they were awake (The DCCT Research Group,1991). In a population study in Edinburgh, retrospective assessment of the frequency ofsevere hypoglycaemia revealed that 90% of patients with impaired awareness of symptomsexperienced severe hypoglycaemia in the preceding year, compared to 18% in a comparablegroup who had retained normal awareness (Hepburn et al., 1990). Prospective studies haveconfirmed the increase in frequency of mild and severe hypoglycaemia associated withimpaired awareness of hypoglycaemia (Gold et al., 1994; Clarke et al., 1995), with a six-fold higher frequency of severe hypoglycaemia being documented in people with impairedawareness (Gold et al., 1994) (Figure 7.4).Incidence(Eventspersubjectperyear)AnnualPrevalence(%Subjects)Figure 7.4 Proportion of patients affected and event rates for severe hypoglycaemia in patientswith type 1 diabetes with normal ( , n = 31) or impaired ( , n = 29) awareness of hypoglycaemia.Reproduced from Cryer and Frier (2004) by permission of John Wiley & Sons, Ltd. Data derived fromGold et al. (1994)PATHOGENESIS OF IMPAIRED AWARENESS OFHYPOGLYCAEMIAThe mechanisms underlying impaired awareness of hypoglycaemia are not known and maybe multifactorial. Possible mechanisms are listed in Box 7.2.
150 IMPAIRED AWARENESS OF HYPOGLYCAEMIABox 7.2 Impaired awareness of hypoglycaemia: possible mechanismsCNS adaptationChronic exposure to low blood glucose• glucose clamp (2.9 mmol/l) for 56 hours in non-diabetic subjects• insulinoma in non-diabetic patients• strict glycaemic control in diabetic patientsRecurrent transient exposure to low blood glucose• antecedent hypoglycaemiaCNS glucoregulatory failure• counterregulatory deficiency (hypothalamic defect?)• hypoglycaemia associated (central) autonomic failure (HAAF)Peripheral nervous system dysfunction• peripheral autonomic neuropathy• reduced peripheral adrenoceptor sensitivityAltered Glycaemic Threshold for Initiation of SymptomsSymptoms of hypoglycaemia commence when the blood glucose reaches a specific level, andalthough this threshold may differ between individuals, it is usually constant and reproduciblein the non-diabetic state (Vea et al., 1992). This blood glucose threshold for symptoms canbe modified by protracted hypoglycaemia (Boyle et al., 1994) and is not fixed in people withdiabetes who are treated with insulin, with its dynamic nature being demonstrated in varioussituations. In clinical practice, it has long been recognised that insulin-treated diabetic patientswho have poor glycaemic control experience symptoms of hypoglycaemia when their bloodglucose declines within a hyperglycaemic range (Maddock and Krall, 1953) and this hasbeen shown to be associated with the onset of hypoglycaemic symptoms at a significantlyhigher blood glucose (4.3 mmol/l) compared to non-diabetic subjects (2.9 mmol/l) (Boyleet al., 1988). Conversely, strict glycaemic control modifies the glycaemic threshold for theonset of symptoms, which do not commence until blood glucose has declined to a lowerlevel than that required in less well controlled patients to initiate a symptomatic response(see Chapter 8).The terminology that is used in relation to a change in the glycaemic threshold is poten-tially confusing. When a lower blood glucose is required to initiate a response, whethersymptomatic, physiological or counterregulatory, the glycaemic threshold is said to be raised
152 IMPAIRED AWARENESS OF HYPOGLYCAEMIAdevelopment of overt neuroglycopenia, which interfered with perception of the autonomicwarning symptoms when they did eventually occur. This sequence of responses disrupts theability of the individual subject to take appropriate action to self-treat low blood glucose.Similar findings have been reported by others (Grimaldi et al., 1990; Mokan et al., 1994;Bacatselos et al., 1995).In these studies, the counterregulatory hormonal responses to hypoglycaemia were delayed(Grimaldi et al., 1990; Hepburn et al. 1991) and their glycaemic thresholds had also shiftedto occur at lower blood glucose concentrations (Mokan et al., 1994). This is consistentwith the reported observation that impaired awareness of hypoglycaemia co-segregates withcounterregulatory hormonal deficiency in people with longstanding type 1 diabetes (Ryderet al., 1990). In addition, Mokan et al. (1994) reported that cognitive dysfunction andneuroglycopenic symptoms in people with impaired awareness occurred at lower bloodglucose levels than in people with type 1 diabetes who had normal awareness. This suggeststhat people with impaired awareness can function effectively with very low blood glucoseconcentrations, at which symptoms and cognitive impairment would normally occur in non-diabetic and aware diabetic subjects. The potential risk of this situation is apparent: it is akinto walking along the edge of a cliff on a dark night. With such a narrow glycaemic warningzone the propensity to rapidly develop severe neuroglycopenia is high and the margin forerror is dangerously narrow.The results of these laboratory-based experimental studies of diabetic patients who haveestablished hypoglycaemia unawareness are consistent with clinical observations of peoplewith this acquired problem. At one moment they appear to be cerebrating normally (despitetheir blood glucose being low) then they rapidly become confused or drowsy, often with avacant or dazed appearance and an inertia to seek some form of carbohydrate to reverse theneuroglycopenia. They may have to rely on relatives, friends or colleagues to identify thehypoglycaemia and provide treatment. This becomes a serious emergency if the patient isalone or if the insidious, but often rapid, development of neuroglycopenia goes unobserved.This explains the increased risk of progression to severe hypoglycaemia, and the higher ratesreported in people with hypoglycaemia unawareness.Studies examining the effects of strict glycaemic control on symptomatic and counter-regulatory responses to hypoglycaemia have also demonstrated a similar shift in glycaemicthreshold for autonomic symptoms and an acute sympatho-adrenal response. However, theeffect on glycaemic thresholds for neuroglycopenic symptoms and cognitive dysfunctionremains controversial (see Chapter 8).Peripheral Autonomic NeuropathyFor many years, peripheral autonomic neuropathy was considered to be the principalcause of impaired awareness of hypoglycaemia (Hoeldtke et al., 1982). This was basedon the assumption that the diminished secretion of epinephrine in response to hypogly-caemia (Hilsted et al., 1981; Bottini et al., 1997) would either prevent the generationof autonomic symptoms (such as sweating or a pounding heart) or reduce their inten-sity, resulting in an inability to perceive the onset of hypoglycaemia. Thus, autonomicneuropathy would interfere with the normal physiological responses stimulated by autonomicactivation.
PATHOGENESIS OF IMPAIRED AWARENESS OF HYPOGLYCAEMIA 153There are various reasons why this hypothesis is unlikely:• Although epinephrine can augment the intensity of a few autonomic symptoms of hypo-glycaemia, it has a very limited role in their generation, which is modulated by sympatheticneural activation; the reduced secretory response of epinephrine in autonomic neuropathyis compensated by an increase in sensitivity of peripheral beta-adrenoceptors (Hilstedet al., 1987).• Diabetic subjects with autonomic neuropathy have normal physiological responses andexperience typical autonomic symptoms during hypoglycaemia (Hilsted et al., 1981;Hepburn et al., 1993b), and no relationship has been found between autonomic dysfunctionand hypoglycaemic symptoms (Berlin et al., 1987).• Impaired awareness of hypoglycaemia co-segregates with deficient counterregulatoryhormonal responses and not with autonomic neuropathy (Ryder et al., 1990).• The prevalence of autonomic neuropathy is similar in patients with type 1 diabetes oflong duration (more than 15 years), whether or not they have impaired awareness ofhypoglycaemia (Hepburn et al., 1990).• Although impaired awareness of hypoglycaemia is a major risk factor for severe hypogly-caemia, the latter is either no more common in type 1 diabetic patients with autonomicneuropathy (Bjork et al., 1990; The DCCT Research Group, 1991), or is only modestlyincreased (Stephenson et al., 1996).• Autonomic neuropathy is not a determinant of whether glycaemic thresholds for auto-nomic (including symptomatic) responses to hypoglycaemia are affected by antecedenthypoglycaemia (Dagogo-Jack et al., 1993).Both impaired awareness of hypoglycaemia and peripheral autonomic neuropathy arecommon in people with type 1 diabetes of long duration, and frequently coexist. This doesnot prove a causal relationship, and it would appear that peripheral autonomic dysfunctiondoes not have a prominent role in the pathogenesis of this syndrome.However, reduced sensitivity of cardiac beta-adrenoceptors to catecholamines has beenobserved in patients with type 1 diabetes who have impaired awareness of hypoglycaemia(Berlin et al., 1987). Hypoglycaemia per se reduces beta-adrenergic sensitivity in type 1diabetes (Fritsche et al., 1998), and this sensitivity is increased after avoidance of hypo-glycaemia for four months in people who have impaired awareness (Fritsche et al., 2001).The improved beta-adrenergic sensitivity correlated with a rise in autonomic symptomscores. Maladaptation of tissue sensitivity to catecholamines may therefore contribute tothe development of hypoglycaemia unawareness even though autonomic neuropathy is notpresent.Hypoglycaemia Associated Autonomic FailureThe co-segregation of impaired hypoglycaemia awareness with counterregulatory deficiencysuggests that they share a common underlying pathogenetic mechanism. These acquiredabnormalities associated with hypoglycaemia in type 1 diabetes (Box 7.3) are charac-terised by a high frequency of severe hypoglycaemia and a common pathophysiological
154 IMPAIRED AWARENESS OF HYPOGLYCAEMIABox 7.3 Acquired syndromes associated with hypoglycaemia in type 1 diabetes• Counterregulatory deficiency• Impaired hypoglycaemia awareness• Altered glycaemic thresholds for counterregulatory and symptomatic responsesFigure 7.6 Schematic diagram of the concept of hypoglycaemia associated autonomic failure(HAAF), based on Cryer (1992)feature, namely the elevated glycaemic thresholds (or lower blood glucose concentra-tions) that are required to trigger symptomatic and hormonal secretory responses. Inother words, more profound hypoglycaemia is necessary to produce the usual symp-tomatic and counterregulatory responses to acute hypoglycaemia. Cryer (1992) has desig-nated this group of abnormalities as a form of ‘hypoglycaemia associated autonomicfailure’ (HAAF), and has speculated that recurrent severe hypoglycaemia may be theprimary problem which establishes a vicious circle (Figure 7.6). It seems likely that thisdefect resides within the central nervous system. The possible mechanisms underlyingHAAF and related hypoglycaemia syndromes in diabetes have been reviewed in detail(Cryer, 2005).
PATHOGENESIS OF IMPAIRED AWARENESS OF HYPOGLYCAEMIA 155Central Nervous System Adaptation to HypoglycaemiaSome people with insulin-treated diabetes remain lucid, with no evidence of impaired cogni-tive function, when their blood glucose is low (often well below 3.5 mmol/l). Biochemicalhypoglycaemia that is asymptomatic is commonly recorded by patients who have impairedawareness of hypoglycaemia, and they appear to have developed a neurological adaptationto chronic neuroglycopenia. The altered glycaemic threshold prevents the onset of warningsymptoms and cognitive dysfunction until the blood glucose falls to a dangerously low level,which is extremely undesirable when striving for safe clinical management of insulin-treateddiabetes.Although the human brain is dependent on a continuous supply of glucose for normalfunction, it can adapt to prolonged exposure to hypoglycaemia. This adaptation processtakes at least several hours and possibly a few days to occur. Short-term exposure toacute hypoglycaemia (blood glucose 2.5 mmol/l) for 60 minutes in non-diabetic subjectsshowed no improvement in cognitive function and no reduction in symptom scoresduring this brief time interval (Gold et al., 1995a). However, when non-diabetic subjectswere subjected to chronic hypoglycaemia (blood glucose 2.9 mmol/l) for 56 hours, usinga glucose clamp, significant cerebral adaptation did occur (Boyle et al., 1994). Theresponses to acute hypoglycaemia (blood glucose 2.5 mmol/l) were compared before andafter the period of chronic hypoglycaemia. Brain glucose uptake was initially reducedwhen blood glucose was below 3.6 mmol/l, but after a period of chronic hypoglycaemiauptake was preserved and cerebral function was maintained (Figure 7.7), demonstratingan effect of cerebral adaptation to chronic neuroglycopenia. The glycaemic thresholds forthe onset of symptoms, counterregulatory hormonal secretion and cognitive dysfunction,were all modified and occurred at much lower blood glucose concentrations. A similarphenomenon has been observed in non-diabetic patients who had an insulinoma causingchronic hypoglycaemia; symptomatic responses to acute hypoglycaemia were blunted andcounterregulatory hormonal responses were impaired but cognitive function was unaf-fected (Mitrakou et al., 1993). Surgical removal of the insulin-secreting tumour reversedthese abnormalities indicating that they had resulted from cerebral adaptation to chronichypoglycaemia.Strict glycaemic control in people with insulin-treated diabetes also alters the glycaemicthresholds for the development of counterregulatory hormones and symptoms (Chapter 8),so that a lower blood glucose concentration is required to trigger these responses. Theobservation that this requires a reduction in HbA1c to within the non-diabetic range(Kinsley et al., 1995) suggests that the median daily blood glucose in these individ-uals is relatively low, and the frequency of biochemical (and symptomatic) hypogly-caemia will be greater than in insulin-treated diabetic patients who are not as wellcontrolled (Thorsteinsson et al., 1986). Boyle et al. (1995) have shown that those patientswho had near normal HbA1c values, maintained normal uptake of glucose by the brainduring hypoglycaemia, so preserving cerebral metabolism, reducing the counterregula-tory responses to hypoglycaemia and diminishing symptomatic awareness. Although thiscapacity to maintain, and even increase, cerebral blood glucose uptake during hypogly-caemia is a protective response for the brain in these patients with strict glycaemiccontrol, it is considered to be maladaptive, because it suppresses the normal symp-tomatic warning of responses and so risks the development of much more profoundneuroglycopenia.
156 IMPAIRED AWARENESS OF HYPOGLYCAEMIAFigure 7.7 Rates of brain glucose uptake, epinephrine concentration and total symptoms of hypogly-caemia in non-diabetic subjects before and after prolonged hypoglycaemia. Initial day of investigation(hatched); after 56 hours of hypoglycaemia (solid). ∗Significant difference from baseline for each ofthe two days. Reproduced from Boyle (1997), Diabetologia, 40, S69–S74. With kind permission ofSpringer Science and Business MediaDuring hypoglycaemia, glucose transport into the brain becomes rate-limiting, and brainenergy metabolism deteriorates. The adaptive response results from an increased utilisationof glucose by the brain. In rodents, the transport of glucose across the blood–brain barrier isincreased after several days of chronic hypoglycaemia (McCall et al., 1986). Further studiesin rats of glucose transport activity across the blood–brain barrier have shown that whenblood glucose was kept below 2.0 mmol/l for several days, changes in expression of theglucose transporter, GLUT-1, in brain microvasculature occurred in response to the chronichypoglycaemia (Kumagai et al., 1995). This increase in GLUT-1 activity was responsiblefor the compensatory increase in glucose transport across the blood–brain barrier.
PATHOGENESIS OF IMPAIRED AWARENESS OF HYPOGLYCAEMIA 157Antecedent (Episodic) HypoglycaemiaIt has been recognised for many years that severe hypoglycaemia is associated with furtherepisodes of severe hypoglycaemia, and one episode may influence the clinical manifestationsof another occurring soon afterwards (Severinghaus, 1926). In recent years, several studieshave shown that the symptomatic and counterregulatory responses to an episode of acutehypoglycaemia are diminished if a preceding (or antecedent) episode of hypoglycaemiahas occurred within the previous 24 hours. Several studies have been performed in non-diabetic subjects (Table 7.2) and in people with insulin-treated diabetes (Table 7.3). Althoughthese studies differ considerably in design and methods of inducing hypoglycaemia, ingeneral it appears that antecedent hypoglycaemia of between one and two hours durationhas a significant influence on the magnitude of the symptomatic and counterregulatoryresponses to subsequent hypoglycaemia occurring within the following 24 to 48 hours(Figure 7.8).The glycaemic thresholds for symptomatic and counterregulatory hormonal responses arealtered by antecedent hypoglycaemia, and the degree to which subsequent responses areblunted are determined by the duration and depth of antecedent hypoglycaemia (Davis et al.,1997). Some of the physiological responses (e.g. sweating) may be blunted for longer thanother responses following antecedent hypoglycaemia (George et al., 1995). Recurrent, short-lived (15 minutes) episodes of hypoglycaemia on four consecutive days, had no effect oncounterregulatory and symptomatic responses in non-diabetic subjects (Peters et al., 1995),and so transient reductions in blood glucose may not produce this effect. Davis et al. (2000)have observed that a short duration of antecedent hypoglycaemia (20 minutes to lowerand raise blood glucose from 3.9 to 2.9 mmol/l with the blood glucose being maintainedfor five minutes at 2.9 mmol/l) did not affect symptomatic awareness of hypoglycaemia,but did blunt the counterregulatory hormonal responses. Antecedent hypoglycaemia alsoreduces the counterregulatory responses to exercise on the following day, both in non-diabetic (Davis et al., 2000b) and type 1 diabetic subjects (Galassetti et al., 2003) andinfluences the metabolic responses, particularly diminishing endogenous glucose produc-tion in response to exercise. This may promote exercise-induced hypoglycaemia in type 1diabetes.Some studies have examined the effect of antecedent hypoglycaemia on cognitive function,but in many the methods of assessment were inadequate and insufficient to provide definitiveevidence of a change in cognitive response. Although some maintain that the glycaemicthreshold for cognitive dysfunction is not altered by hypoglycaemia (see Chapter 8), anincreasing number of studies have suggested that this does shift to a lower blood glucoseconcentration in the same manner as the thresholds for autonomic and counterregula-tory responses (Veneman et al., 1993; Ovalle et al., 1998; Fanelli et al., 1998). Consis-tent with these observations, a study from Germany in non-diabetic men has shown thatafter a single episode of antecedent hypoglycaemia, subsequent hypoglycaemia had lesseffect on auditory-evoked brain potentials and short-term memory (Fruehwald-Schulteset al., 2000), demonstrating cerebral adaptation that preserves cognitive function. Nocturnal(episodic) hypoglycaemia, which is frequently not identified by patients, has been proposedas a mechanism for the induction of hypoglycaemia unawareness in people who giveno history of recurrent hypoglycaemia (Veneman et al., 1993). The possible mechanismsof cerebral adaptation causing impaired awareness of hypoglycaemia are summarised inBox 7.4.
160 IMPAIRED AWARENESS OF HYPOGLYCAEMIAFigure 7.8 Schematic representation of the effect of antecedent hypoglycaemia on the neuroendocrineand symptomatic responses to subsequent hypoglycaemiaBox 7.4 Mechanisms of cerebral adaptation causing impaired awareness ofhypoglycaemiaSymptomatic and Neuroendocrine responses to hypoglycaemia in insulin-treateddiabetes are diminished in association with:• strict glycaemic control (HbA1c in non-diabetic range)• antecedent (episodic) hypoglycaemia• chronic (protracted) hypoglycaemiaThey may be restored by:• relaxation of glycaemic control• scrupulous avoidance of hypoglycaemiaAlthough antecedent hypoglycaemia may induce transient impairment of awareness ofhypoglycaemia it is unclear how this mechanism would induce chronic or prolonged loss ofsymptomatic perception. Although frequent, recurrent hypoglycaemia may have a contribu-tory effect to inducing hypoglycaemia unawareness, presumably the hypoglycaemia has tobe relatively protracted to induce prolonged cerebral adaptation, and the phenomenon is notlimited to patients who have strict glycaemic control. The problem remains of explainingthe induction of protracted or chronic hypoglycaemia unawareness, which often appears tobe a permanent defect. Presumably repetitive hypoglycaemic insults to the brain (which arenot necessarily severe) eventually ‘downregulate’ the central mechanisms that sense a lowblood glucose and activate the glucoregulatory responses within the hypothalamus. There isevidence of a permanent redistribution of regional cerebral blood flow in diabetic patientswith a history of recurrent severe hypoglycaemia (MacLeod et al., 1994a) with, in particular,a relative increase in blood flow to the frontal lobes. This may represent a chronic adaptive
IMPAIRED AWARENESS OF HYPOGLYCAEMIA 161response to protect vulnerable areas of the brain from recurrent, severe neuroglycopenia.However, a further study showed that the changes in regional cerebral blood flow in responseto controlled hypoglycaemia in patients with type 1 diabetes occurred independently of thestate of awareness of hypoglycaemia (MacLeod et al., 1996). The EEG changes associatedwith modest hypoglycaemia are more pronounced in patients with type 1 diabetes who haveimpaired awareness of hypoglycaemia (Tribl et al. 1996). Most studies suggest that a diffusefunctional abnormality is present in the anterior part of the brain in diabetes, and this may beimplicated in the impaired perception of hypoglycaemia. The pre-frontal areas of the cortexare closely connected to sub-cortical areas, and localised dysfunction could theoreticallyreduce the ability of the brain to perceive symptomatic hypoglycaemia.Further clues may be provided by neuroimaging studies. A study using positron emissiontomography (PET) compared changes in global and regional brain glucose metabolism duringeuglycaemia and hypoglycaemia in 12 men with type 1 diabetes, six of whom had impairedawareness of hypoglycaemia (Bingham et al., 2005). Brain glucose content was reducedby hypoglycaemia in both groups with a relative increase in tracer uptake on the prefrontalcortical regions. Differences between the groups were observed in glucose handling in regionsof the brain, and whereas the cerebral metabolic rate for glucose showed a relative rise in theaware subjects, it fell in the unaware subjects. Global neuronal activation was observed withhypoglycaemia in the aware patients, but was absent in the unaware, suggesting that corticalactivation is a necessary correlate of hypoglycaemia awareness. Further studies using PETscans or other forms of neuroimaging may identify regional differences in the response tohypoglycaemia within the brains of people with impaired awareness, which will help toelucidate the functional abnormalities associated with this syndrome.IMPAIRED AWARENESS OF HYPOGLYCAEMIA ANDLONG-TERM EFFECT ON COGNITIVE FUNCTIONImpaired awareness of hypoglycaemia is a major risk factor for severe hypoglycaemia, andpatients with the chronic form of this condition have a six-fold higher frequency (Gold et al.,1994). It is possible therefore that impaired hypoglycaemia awareness may be associatedwith evidence of a decline in cognitive function. Hepburn et al. (1991) noted that diabeticpatients with a history of impaired awareness of hypoglycaemia performed less well thanthose with normal awareness of hypoglycaemia on limited cognitive function testing, bothat a normal blood glucose and during hypoglycaemia. This suggested that an acquiredcognitive impairment may have been superimposed upon an increased susceptibility toneuroglycopenia. A modest, but insignificant, decline in intellectual function was notedwith progressive loss of hypoglycaemia awareness in a population study (MacLeod et al.,1994b).Formal measurement of cognitive function during controlled hypoglycaemia (bloodglucose 2.5 mmol/l) showed that patients with type 1 diabetes who had impaired hypogly-caemia awareness exhibited more profound cognitive dysfunction during acute hypogly-caemia than patients with normal awareness, and that this persisted for longer followingrecovery of blood glucose (Gold et al., 1995b). By contrast, a more recent study of peoplewith type 1 diabetes, which examined the rate of recovery of differing domains of cognitivefunction after hypoglycaemia, showed that during hypoglycaemia (blood glucose 2.5 mmol/l)cognitive function did not deteriorate in those with impaired awareness, suggesting that
162 IMPAIRED AWARENESS OF HYPOGLYCAEMIAcerebral adaptation to hypoglycaemia had occurred in these patients (Zammitt et al., 2005).These apparently discrepant results leave this issue unresolved.HUMAN INSULINFor 60 years after its discovery, insulin for therapeutic use was obtained from the pancreataof cattle and pigs. With the development of recombinant DNA technology it was possibleto ‘genetically engineer’ molecules and insulin was the first protein to be made in thisway, becoming available for the treatment of humans in the 1980s. Several of the existinganimal insulin formulations were withdrawn, principally for commercial reasons, and humaninsulin rapidly became the most commonly prescribed form of insulin. The structure ofhuman insulin differs from porcine insulin by a single amino acid and from bovine insulinby three amino acids. In initial trials it was not expected that human insulin would differsubstantially in potency from animal insulin, but because human insulin was slightly purerthan some of the animal insulins, patients were advised to reduce the dose by around 10%when converting from animal to human insulin. Detailed pharmacokinetic studies comparinghuman and animal insulins did not demonstrate any major differences, but human insulin hasa slightly faster onset of action, a slightly shorter duration of action, and is less immunogenicthan equivalent animal insulins. Most clinical studies, conducted on a worldwide scale,showed no significant differences between human and animal insulins in their clinicalapplication.In Switzerland, however, one group of clinicians reported encountering serious clinicalproblems with the use of human insulin in patients with type 1 diabetes (Teuscher and Berger,1987). In particular, they claimed that patients experienced more frequent hypoglycaemiawith human insulin, and that warning symptoms were modified by human insulin, as a resultof which many patients were unable to detect the onset of hypoglycaemia. A pathologist in theUnited Kingdom then claimed that the number of patients dying from severe hypoglycaemiahad increased since the introduction of human insulin (see Chapter 12). The evidence forthis irresponsible statement did not withstand scrutiny, but in the UK anecdotal reportsemerged of problems experienced by patients with human insulin, and solicitors acting onbehalf of over 400 patients tried to bring a legal action against the insulin manufacturers,alleging that human insulin gave less warning of hypoglycaemia. Additional claims includedallegations that human insulin may have caused personality changes in individuals and evenother disease states such as multiple sclerosis. This group action was abandoned in 1993because of the lack of robust scientific evidence for these claims.However, this issue generated much controversy and heated debate and stimulated severalstudies comparing human with animal insulins, which are not reviewed here. A system-atic review of the extensive literature on this topic examined whether published evidencesupported a difference in the frequency and awareness of hypoglycaemia induced by humanand animal insulins (Airey et al., 2000). A total of 52 randomized controlled trials wereidentified, 37 of which were of double-blind design, whereas others reported hypoglycemicoutcomes as a secondary or incidental outcome during comparative investigations of efficacyor immunogenicity. Seven of the double-blind studies reported differences in frequency ofhypoglycaemia or of symptomatic awareness, and four of the unblinded trials reported differ-ences in hypoglycaemia. None of the four population time trend studies found any relation-ship between the increasing use of human insulin and hospital admission for hypoglycaemia
TREATMENT STRATEGIES 163or unexplained death among people with insulin-treated diabetes. The authors observed thatthe least rigorous scientific studies gave the greatest support to the premise that treatmentwith human insulin influences the frequency, severity or symptoms of hypoglycaemia. Thereport concluded that the published evidence did not support the contention that humaninsulin is responsible either for the alleged problems with impaired awareness of hypogly-caemia or for a higher risk of severe hypoglycaemia, but were unable to decide whether someof the phenomena associated with the use of human insulin resulted from stricter glycaemiccontrol (Airey et al., 2000).In clinical practice there are undoubtedly a small number of people with insulin-treateddiabetes in whom the use of human insulin has not been satisfactory, being associated withfrequent and unpredictable hypoglycaemia and a diminished sense of well-being. Whetherthis is related to the different pharmacokinetics of human insulin or represents an idiosyn-cratic response in individuals is unclear, but such patients clearly wish to retain the option touse animal species of insulin, and it is to be hoped that the availability of the animal speciesof insulins will be maintained. No problem with symptomatic awareness of hypoglycaemiahas been reported with the use of the newer insulin analogues.TREATMENT STRATEGIESWhen impaired awareness of hypoglycaemia is therapy-related, that is, resulting from strictglycaemic control, the approach to management is relatively simple. The total insulin doseshould be reduced, attention paid to the appropriateness of the insulin regimen, and overallglycaemic control should be relaxed. Liu et al. (1996) reported an improvement in symp-tomatic and counterregulatory hormonal responses to hypoglycaemia after three months ofless strict glycaemic control in a small group of insulin-treated patients, in whom the meanHbA1c rose from 6.9% to 8.0%.It has been claimed that impaired awareness of hypoglycaemia (and to some extent counter-regulatory hormonal deficiency) can be reversed by scrupulous avoidance of hypoglycaemiathrough meticulous attention to diabetic management (Cranston et al., 1994; Dagogo-Jacket al., 1994; Fanelli et al., 1994). The effect that this had on glycaemic thresholds for cogni-tive dysfunction and the recovery of counterregulatory hormonal secretion to hypoglycaemiadiffered between these studies, but all demonstrated an improved symptomatic responsefollowing avoidance of hypoglycaemia for periods varying from three weeks to one year.However, the studies can be criticised for the following reasons:• Only a small number of patients were studied.• The definition of hypoglycaemia unawareness was based on an increased frequency ofasymptomatic biochemical hypoglycaemia, and with the exception of the study by Dagogo-Jack et al. (1994), was not based on having a history of hypoglycaemia unawareness.• In all studies there was a small but definite rise in glycated haemoglobin, suggesting thatthe improved symptomatic awareness was related primarily to relaxation of glycaemiccontrol.Although the scrupulous avoidance of hypoglycaemia is clearly desirable, and may bebeneficial to reducing the severity of hypoglycaemia unawareness, it is very difficult to
164 IMPAIRED AWARENESS OF HYPOGLYCAEMIAFigure 7.9 Augmentation of the normal secretory response of epinephrine (adrenaline) to, andawareness of, acute hypoglycaemia (blood glucose 2.8 mmol/l) by the prior ingestion of caffeine ininsulin-treated diabetic patients. Derived from data in Debrah et al. (1996)achieve as it is extremely time-consuming and labour-intensive both for patients and healthprofessionals. The use of continuous subcutaneous insulin infusion overnight instead ofisophane (NPH) insulin at bedtime has been shown to be beneficial in diabetic patientswith impaired awareness of hypoglycaemia, improving warning symptoms and counterreg-ulatory responses to hypoglycaemia, presumably by reducing the frequency of nocturnalhypoglycaemia (Kanc et al., 1998).The ingestion of caffeine uncouples the relationship between cerebral blood flow andglucose utilisation via antagonism of adenosine receptors, causing relative neuroglycopeniaand earlier release of counterregulatory hormones during moderate hypoglycaemia. Theprior consumption of caffeine augments the symptomatic and counterregulatory hormonalresponses to a modest reduction of blood glucose in non-diabetic subjects (Kerr et al., 1993),and a similar phenomenon occurs in people with type 1 diabetes following the ingestion of adose of caffeine equivalent to two or three cups of coffee (Debrah et al., 1996). The reductionin cerebral blood flow is sustained, the counterregulatory response is augmented (Figure 7.9)and greater awareness of hypoglycaemia occurs (see Chapter 5). This raises the prospectof identifying some form of therapeutic intervention, which utilises a similar mechanism toheighten the residual symptomatic response in people with type 1 diabetes who have impairedawareness of hypoglycaemia. The adenosine-receptor antagonist, theophylline, stimulatesthe secretion of catecholamines and reduces cerebral blood flow, and a single intravenousdose has been shown to enhance counterregulatory hormone responses to hypoglycaemiaand partially restore perception of hypoglycaemic symptoms in patients with type 1 diabeteswith impaired awareness of hypoglycaemia (de Galan et al., 2002). Glycaemic thresholdsfor haemodynamic and symptomatic responses were restored to normal. It is not knownwhether oral theophylline would be as effective, and whether the effects can be sustained,as the development of tolerance to these drugs is common.It is clearly desirable to avoid severe hypoglycaemia at all costs, and treatment strategiesshould be adopted to achieve this aim (Box 7.5). Frequent blood glucose monitoring isessential in affected patients, and may require occasional nocturnal measurements to detect
CONCLUSIONS 165Box 7.5 Treatment strategies for patients with impaired awareness ofhypoglycaemia• Frequent blood glucose monitoring (including nocturnal measurements).• Avoid blood glucose values < 4 0mmol/l.• Set target range of blood glucose higher than for ‘aware’ patients (e.g. preprandialbetween 6.0–12.0 mmol/l; bedtime > 8 0mmol/l)• Avoid HbA1c in non-diabetic range.• Use predominantly short-acting insulins (e.g. basal-bolus regimen; insulinanalogues).• Regular snacks between meals and at bedtime, containing unrefined carbohydrate.• Appropriate additional carbohydrate consumption and/or insulin dose adjustmentfor premeditated exercise.• Learn to identify subtle neuroglycopenic cues to low blood glucose.low blood glucose during the night. Blood glucose awareness training has been developedin the USA, with re-education of affected patients to recognise neuroglycopenic cues (Coxet al., 1995), but this also requires facilities and resources that are not available in mostcentres. Intensive insulin therapy is contraindicated in patients who have impaired awarenessof hypoglycaemia and treatment goals have to be considered individually. The avoidanceof severe hypoglycaemia is paramount as this may exacerbate the problem, and the use ofmostly short-acting insulin (and possibly insulin analogues) in basal-bolus regimens maybe particularly useful in avoiding biochemical and symptomatic hypoglycaemia withoutcompromising overall glycaemic control.CONCLUSIONS• An inadequate symptomatic warning to hypoglycaemia is common in people withinsulin-treated diabetes and is described as impaired awareness of hypoglycaemia orhypoglycaemia unawareness. It increases in prevalence with duration of insulin-treateddiabetes.• In people who report impaired awareness of hypoglycaemia, asymptomatic hypoglycaemiaoccurs more frequently during routine blood glucose monitoring. This may alert theclinician to the possibility that an individual is developing this problem.• Impaired awareness of hypoglycaemia may be associated with strict glycaemic control;significant modification of the symptomatic response occurs when the HbA1c concentrationis within the non-diabetic range.
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170 IMPAIRED AWARENESS OF HYPOGLYCAEMIAPampanelli S, Fanelli C, Lalli C, Ciofetta M, Del Sindorco P, Lepore M et al. (1996). Long-termintensive insulin therapy in IDDM: effects on HbA1c, risk for severe and mild hypoglycaemia, statusof counterregulation and awareness of hypoglycaemia. Diabetologia 39: 677–86.Peters A, Rohloff F, Kerner W (1995). Preserved counterregulatory hormone release and symptomsafter short term hypoglycemic episodes in normal men. Journal of Clinical Endocrinology andMetabolism 80: 2894–8.Pramming S, Thorsteinsson B, Bendtson I, Binder C (1991). Symptomatic hypoglycaemia in 411 type1 diabetic patients. Diabetic Medicine 8: 217–22.Robinson AM, Parkin HM, Macdonald IA, Tattersall RB (1995). Antecedent hypoglycaemia in non-diabetic subjects reduces the adrenaline response for 6 days but does not affect the catecholamineresponse to other stimuli. Clinical Science 89: 359–66.Ryder REJ, Owens DR, Hayes TM, Ghatei MA, Bloom SR (1990). Unawareness of hypoglycaemia andinadequate hypoglycaemic counterregulation: no causal relation with diabetic autonomic neuropathy.British Medical Journal 301: 783–7.Severinghaus EL (1926). Hypoglycemic coma due to repeated insulin overdosage. American Journalof Medical Sciences 172: 573–80.Stephenson JM, Kempler P, Cavallo Peria P, Fuller JH, EURODIAB IDDM Complications StudyGroup (1996). Is autonomic neuropathy a risk factor for severe hypoglycaemia? The EURODIABIDDM Complications Study. Diabetologia 39: 1372–6.Sussman KE, Crout JR, Marble A (1963). Failure of warning in insulin-induced hypoglycemic reac-tions. Diabetes 12: 38–45.Teuscher A, Berger WG (1987). Hypoglycaemia unawareness in diabetics transferred from beef/porcineinsulin to human insulin. Lancet ii: 382–5.The DCCT Research Group (1991). Epidemiology of severe hypoglycemia in the Diabetes Controland Complications Trial. American Journal of Medicine 90: 450–9.The Diabetes Control and Complications Trial Research Group (1993). The effect of intensive treatmentof diabetes on the development and progression of long-term complications in insulin-dependentdiabetes mellitus. The New England Journal of Medicine 329: 977–86.Thorsteinsson B, Pramming S, Lauritzen T, Binder C (1986). Frequency of daytime biochemical hypo-glycaemia in insulin-treated diabetic patients: relation to daily median blood glucose concentrations.Diabetic Medicine 3: 147–51.Tribl G, Howorka K, Heger G, Anderer P, Thoma H, Zeitlhofer J (1996). EEG topography duringinsulin-induced hypoglycemia in patients with insulin-dependent diabetes mellitus. EuropeanNeurology 36: 303–9.Vea H, Jorde R, Sager G, Vaaler S, Sundsfjord J (1992). Reproducibility of glycaemic thresholdsfor activation of counterregulatory hormones and hypoglycaemic symptoms in healthy subjects.Diabetologia 35: 958–61.Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J (1993). Induction of hypoglycemia unawarenessby asymptomatic nocturnal hypoglycemia. Diabetes 42: 1233–7.Widom B, Simonson DC (1992). Intermittent hypoglycemia impairs glucose counterregulation.Diabetes 41: 1335–40.Zammitt NN, Warren RE, Deary IJ, Frier BM (2005). Recovery of cognitive function after insulin-induced hypoglycaemia in people with type 1 diabetes with either normal or impaired awareness ofhypoglycaemia. Diabetologia 48 (Suppl 1): A293 (abstract).
172 RISKS OF STRICT GLYCAEMIC CONTROLWhen cohorts of patients are studied rather than individuals, other potential risks ofthe demands of intensified insulin therapies, and in particular the inherent psychosocialstrains, do not emerge as a problem. Concerns have been expressed that greater use ofhome blood glucose monitoring may increase anxiety, particularly in type 2 patients whoare not taking insulin, and who have limited means at their disposal of responding tohigh blood glucose values (Franciosi et al., 2001). In contrast, in type 1 diabetes, researchsuggests that patients may prefer intensified treatment regimens. In the Diabetes Controland Complications Trial, patients in the intensive treatment arm of the study had an overallimprovement in their subjective feelings of control and well-being, although it was offset bya greater fear of hypoglycaemia (The Diabetes Control and Complications Trial ResearchGroup, 1996a). However, this balance may be particularly positive in people who activelychoose to use intensified therapies. In the DAFNE Trial, all participants had selected theintensive programme of treatment, and significant and apparently lasting benefits in qualityof life measures were demonstrated using the intensified management strategy (DAFNEResearch Group, 2002). However, it must be acknowledged that when individual patientsare exhorted to achieve perfection in glycaemic control, they may experience difficultiesand frustration with the impossible task of trying to eliminate blood glucose readings thatlie outside the normal range, especially if they are not equipped to act upon such readings.In general, the main risk of intensified diabetes therapy remains hypoglycaemia. Thischapter examines the problem of hypoglycaemia that is specifically associated with strictglycaemic control, an area that has aroused much concern and controversy. Most commentsrelate to patients with type 1 diabetes. The risks of severe hypoglycaemia associated withstrict control in insulin-treated type 2 diabetes are likely to be similar, but occur much laterin the natural history of the disease, when insulin deficiency is profound (see Chapter 11).DEFINITION OF HYPOGLYCAEMIAIt is difficult to determine a frequency of hypoglycaemia without first defining what is meant by‘hypoglycaemia’. In many studies, hypoglycaemia is documented by self-reporting, which maybe very unreliable (Heller et al., 1995). Retrospective analyses suffer from problems of recall,and accurate documentation of hypoglycaemia is obtained only in prospective research stud-ies that require biochemical verification of low blood glucose concentrations (see Chapter 3).Hypoglycaemia can be categorised by its symptomatology and its severity, but no realconsensus exists. ‘Mild’ hypoglycaemia is usually defined as an episode that a person recog-nises and treats themselves and does not significantly disrupt daily living; ‘severe’ hypo-glycaemia is an episode in which blood glucose has fallen to a level where the patient hasbecome so disabled that assistance is required from another person (The Diabetes Controland Complications Trial Research Group, 1991). Alternatively, ‘severe’ hypoglycaemia maybe defined by the requirement for parenteral treatment (intramuscular glucagon or intra-venous dextrose), with or without hospital admission, or by the development of coma (TheDiabetes Control and Complications Trial Research Group, 1987). A category of ‘moderate’hypoglycaemia, in which an individual requires external assistance but which falls shortof requiring parenteral therapy or developing a coma, or the division of hypoglycaemiainto grades of severity has also been used (Limbert et al., 1993). Obviously the defini-tion used will affect the estimate of incidence, and if severe hypoglycaemia is definedsolely as coma, rates will be lower than if all episodes requiring assistance are included.
CONTRIBUTORS TO INCREASED RISK OF SEVERE HYPOGLYCAEMIA 173Various levels of blood glucose concentration have been used to define mild and moderatehypoglycaemia biochemically, but there is now recognition that the blood glucose concentra-tions which have been used arbitrarily to define pathological ‘spontaneous’ hypoglycaemia(such as < 2 2 mmol/l) are unsuitable for defining hypoglycaemia in people with diabetes.An arterialised plasma glucose concentration of around 3.6 mmol/l may be sufficient tocause physiological autonomic responses in healthy volunteers (Chapter 1). Subtle changesin cognitive function can initially be detected by formal testing below 4.0 mmol/l, althoughclinically relevant cognitive impairment does not occur until the arterialised plasma glucoseconcentration has fallen to approximately 3.0 mmol/l (Chapter 2). There is evidence thatif plasma glucose falls below 3.0 mmol/l for a period of time, this can reduce the symp-tomatic responses to a further episode of hypoglycaemia occurring within the following 24hours (Heller and Cryer, 1991), so-called antecedent hypoglycaemia (Chapter 7). The contin-uous avoidance of low blood glucose concentrations (below 3.0 mmol/l) can restore normalhormonal and symptomatic responses to hypoglycaemia (Fanelli et al., 1993; Cranston et al.,1994), and it follows that values below 3.0 mmol/l can be considered to be hypoglycaemic.Diabetes UK coined the phrase ‘make four the floor’ to protect against potentially dangeroushypoglycaemia and, most recently, a panel convened by the American Diabetes Associationconcluded in favour of a concentration of 3.9 mmol/l (Working Group on Hypoglycemia,American Diabetes Association, 2005). This was based on research data, showing evidenceof counterregulatory responses at blood glucose concentrations (often arterial or arterialised)of 3.9 mmol/l and the demonstration of a small reduction in the glucagon response tohypoglycaemia induced immediately afterwards. However, this defines ‘hypoglycaemia’ atblood glucose concentrations that commonly occur in healthy non-diabetic people and maytherefore encourage over-treatment. It is probably more appropriate to differentiate betweentargets for adjusting therapy, which may properly be above 4.0 mmol/l, and ‘hypoglycaemia’,which implies a pathological cause and requires intervention.CONTRIBUTORS TO INCREASED RISK OF SEVEREHYPOGLYCAEMIA IN PATIENTS UNDERTAKING INTENSIFIEDINSULIN THERAPYFactors Predisposing Patients to Severe Hypoglycaemia in IntensifiedInsulin TherapyThe relationship between impaired symptomatic awareness of hypoglycaemia and anincreased rate of severe hypoglycaemia is well established (Hepburn et al., 1990; Gold et al.,1994; Clarke et al., 1995), although affected patients in these studies were not subject to strictglycaemic control. The association between counterregulatory failure and increased risk ofsevere hypoglycaemia is also well recognised (Ryder et al., 1990). Indeed, counterregula-tory failure was proposed as a predictor of risk of severe hypoglycaemia in the subsequentapplication of intensified therapy (White et al., 1983), and it was not until later that theability of intensified therapy to cause counterregulatory failure was suggested (Simonsonet al., 1985a). It is indeed very important to appreciate that neither asymptomatic nor severehypoglycaemia are restricted to people using intensified insulin therapy.
174 RISKS OF STRICT GLYCAEMIC CONTROLApart from a previous history of severe hypoglycaemia, the greatest risk may be the degreeof insulin deficiency, as reflected by the absence of C-peptide (Muhlhauser et al., 1998), aswell as the glycaemic control prior to embarking upon intensified therapy and the determi-nation to reach the glycaemic targets (Bott et al., 1994; Muhlhauser et al., 1998). Preser-vation of endogenous insulin is not affected by intensification of insulin therapy, althoughthere is evidence to suggest that if strict glycaemic control is imposed when diabetes is diag-nosed, this may result in more prolonged preservation of endogenous insulin secretion (Shahet al., 1989, The Diabetes Control and Complications Trial Research Group, 1998b). Otherfactors, related to the patient rather than to treatment, may increase the risk of severe hypogly-caemia, including social class (Muhlhauser et al., 1998) and possibly genetics. In a study fromDenmark,muchoftheriskofseverehypoglycaemiawasattributedtoACEgenotype(Pedersen-Bjergaard et al., 2003), although this has not been confirmed and has aroused controversy;also, the absence of traditional risk factors in the Danish study is a cause for concern.The Effects of Intensified Insulin Therapy Upon Risk of SevereHypoglycaemiaIn the DCCT, a clear link was demonstrated between intensified insulin therapy and thefrequency of severe hypoglycaemia. In that trial, a three-fold higher rate of severe hypogly-caemia was recorded by the patients in the intensive treatment arm when compared with thoseon conventional therapy (The Diabetes Control and Complications Trial Research Group,1991; 1993; 1997). This persisted throughout the entire study, although absolute rates declinedgradually in both groups. Furthermore, the risk of severe hypoglycaemia was higher for anygiven HbA1c, for the people receiving intensive treatment. This phenomenon has not beenadequately explained. It is now known that exposure to hypoglycaemia per se can inducedefects in counterregulation and loss of subjective awareness of hypoglycaemia (Heller andCryer, 1991; George et al., 1995; 1997; Davis et al., 1997). It has been assumed that inten-sive therapy exposes the patient to a greater frequency of mild hypoglycaemia that is suffi-cient to induce such defects and thereby increase the risk of severe hypoglycaemia by thatmechanism. However, methods for delivering intensified diabetes therapy have subsequentlyimproved. Modern methods that focus on transferring skills of insulin adjustment to the patientsthemselves are reported to achieve improvements in HbA1c with multiple daily injectiontherapy regimens, without causing more episodes of severe hypoglycaemia, and in their mostsuccessful forms achieve a parallel reduction of hypoglycaemia (Jorgens et al., 1993; DAFNEStudy Group, 2002; Plank et al., 2004; Samann et al., 2005). The judicious use of insulinanalogues in intensified regimens may be associated with slightly less risk of hypoglycaemia(Ashwell et al., 2006), whereas the use of continuous subcutaneous insulin infusion (CSII)with pumps is associated with a much lower frequency of severe hypoglycaemia, and has beenused successfully as treatment for patients with problematical hypoglycaemia (Bode et al.,1996, Rodrigues et al., 2005) and in the context of clinical trials (Hoogma et al., 2006).The Link Between Intensified Insulin Therapy and Risk of SevereHypoglycaemiaPatients describe symptoms of hypoglycaemia at a wide range of blood glucose concen-trations. In an individual patient, the main determinant of the blood glucose concentration
176 RISKS OF STRICT GLYCAEMIC CONTROLoccurrence of asymptomatic biochemical hypoglycaemia. The risk may be particularly mani-fested when the glycated haemoglobin concentration is reduced to within, or just above, thenon-diabetic range (Box 8.1). This was shown in a study of 34 subjects with type 1 diabeteswho had a wide range of total HbA1 values (Kinsley et al., 1995). They were subjected to astepped glucose clamp to lower arterialised blood glucose to 2.3 mmol/l and the responses werecompared with a non-diabetic control group. Symptomatic responses (particularly autonomic)and some counterregulatory hormonal responses were diminished in the seven diabetic subjectswho had a total HbA1 of 7.85% or less, i.e., glycaemic control that was within their local non-diabeticrangeoftotalHbA1.AverysimilarstudybyPampanellietal.(1996)producedidenticalobservations in 10 of 33 subjects, whose HbA1c was within the local non-diabetic range, and inwhom it was also noted that the onset of some aspects of cognitive dysfunction was delayed.Current evidence would suggest that it is the increased exposure to episodic hypoglycaemia,associated with the treatment strategy that is promoting the problem. Most importantly, a seriesof studies has shown that hypoglycaemia awareness and counterregulatory hormone responsescan be restored in well-controlled diabetic subjects by avoidance of blood glucose concen-trations below 3.0 mmol/l in daily life, confirming the circular link between hypoglycaemiaexposureandimpairedawarenessofhypoglycaemia(Fanelli etal.,1993;Cranston etal.,1994).Thus, although impaired awareness of hypoglycaemia is a major problem in clinicalpractice, it is by no means exclusively confined to intensified therapy. Although the riskremains greater with lower mean glucose and glycated haemoglobin concentrations, impairedawareness is reversible, at least in the setting of carefully controlled research studies, byscrupulous avoidance of even modest hypoglycaemia in daily life (Fanelli et al., 1993;Cranston et al., 1994). Although this may result in a deterioration of glycaemic control asthe problem was reversed, with a rise in mean HbA1c from 6.9% to 8.0% in one smallstudy of seven patients with impaired awareness of hypoglycaemia (Liu et al., 1996), thisis not inevitable (Cranston et al., 1994). It is possible for avoidance of hypoglycaemia toresult in an improvement of glycated haemoglobin, as post-hypoglycaemia hyperglycaemiais eradicated.Much less work has been done in type 2 diabetes, although there is increasing evidencethat in patients with insulin-treated type 2 diabetes of long duration, the prevalence of severehypoglycaemia is not greatly different from people with type 1 diabetes (see Chapter 11).Modern trends of starting insulin earlier in type 2 diabetes, when insulin deficiency is notBox 8.1 Effects of strict glycaemic control in type 1 diabetes• Reduction in microvascular and macrovascular complications.• Potential increase in risk of severe hypoglycaemia.• Diminished counterregulatory and symptomatic responses to hypoglycaemia.• Altered glycaemic thresholds for activation of responses (i.e., lower blood glucoserequired).• Promotion of increased frequency of exposure to hypoglycaemia which exacerbatesimpaired awareness of hypoglycaemia.• Tendency to weight gain.
CEREBRAL ADAPTATION 177severe, are likely to reduce the overall risk of hypoglycaemia in patients with insulin-treatedtype 2 diabetes. Recent studies using bedtime basal insulin as the first line of intensifyingdiabetes treatment for type 2 patients who are not achieving glycaemic targets, have reporteda low risk of severe hypoglycaemia, even when using conventional insulins (Yki-Jarvinenet al., 2006). However, caution is indicated when patients require conversion to full insulintherapy. In a small study of poorly-controlled patients treated with oral medication, in whichresponses to hypoglycaemia were measured before and after improving glycaemic controlwith insulin, counterregulatory responses and the blood glucose thresholds at which thesewere initiated were modified, as occurs in type 1 diabetes (Korson-Burakowska et al., 1998).CEREBRAL ADAPTATIONWhen hypoglycaemia occurs, the stimulus for counterregulation appears to be a fall in thecerebral metabolic rate of glucose. Boyle et al. (1994) measured arteriovenous differencesin glucose concentration in the human brain during hypoglycaemia to show that the rate ofuptake of glucose (and by implication of metabolism) falls before most of the counterregula-tory responses and cognitive changes occur. They also demonstrated that this fall in metabolicrate of the brain was reduced in healthy volunteers who were made acutely hypoglycaemicfollowing a period of 56 hours of protracted moderate hypoglycaemia, suggesting that themetabolism of the human brain can adapt to prolonged exposure to low blood glucose.This enables the brain to maintain its metabolism and continue to function in response tosubsequent hypoglycaemia. A further study in diabetic patients showed that diabetic patientswith strict glycaemic control and impaired awareness of hypoglycaemia were able to main-tain the rate of cerebral uptake of glucose during experimental hypoglycaemia, while otherswith normal symptomatic awareness exhibited a marked fall in cerebral uptake of glucose,associated with symptomatic and counterregulatory hormonal responses (Figure 8.2) (Boyleet al., 1995). These data led to the hypothesis that impaired awareness of hypoglycaemiaand defective glucose counterregulation may result from an adaptation in the sensitivity ofthe cerebral glucose sensor, which allows it to sustain its metabolic rate (and so not triggercounterregulation) during subsequent hypoglycaemia (see Chapter 7).However, the expectation that patients with impaired awareness of hypoglycaemia willshow an increase in brain glucose metabolic rate at any given blood glucose concentrationhas not been supported by neuroimaging studies. In studies utilising positron emissiontomography that used various tracers for glucose to measure either the metabolic rate ofbrain glucose or glucose tracer uptake in humans, several investigators have failed to finddifferences during euglycaemia or hypoglycaemia that could be in accord with prevailingglycaemic control (Cranston et al., 2001; Segal et al., 2001). One study found evidence duringhypoglycaemia of a difference in the change in uptake of the glucose tracer, de-oxyglucose,in the brain region around the hypothalamus in intensively-treated diabetic subjects who hadimpaired awareness of hypoglycaemia (Cranston et al., 2001), which is of interest becauseanimal studies have implicated this region (among others) in sensing hypoglycaemia. Inmore recent studies, the difference in brain glucose metabolism in subjects with impairedawareness of hypoglycaemia was a failure of increase of cerebral metabolic rate duringhypoglycaemia, associated with a failure to generate or perceive symptoms (Bingham et al.,2005). These data are compatible with the concept that cortical activation is important forperception of symptoms and that this fails in people who develop a loss of awareness of
CEREBRAL ADAPTATION 179hypoglycaemia. It is becoming evident that changes in symptomatic responses and corticalfunction in hypoglycaemia are driven by complex mechanisms associated with, but notexclusively controlled directly by, the changes in the glucose metabolic rate of neurones.Some cognitive functions are better preserved than others during hypoglycaemia in subjectswho have previous experience of hypoglycaemia than in hypoglycaemia-naive subjects whohave normal counterregulation (Fanelli et al., 1993; Boyle et al., 1995). This does not entirelyfit the clinical picture of patients becoming significantly confused during hypoglycaemiawhile remaining asymptomatic.One measure of cognitive function, the choice reaction time, does not appear to adapt, andwhen hypoglycaemia is induced slowly, it deteriorates at similar levels of blood glucose inmost subjects, irrespective of their previous glycaemic experience and their state of hypogly-caemia awareness (Maran et al., 1995). Other measures of cognitive function also deteriorateat similar levels of blood glucose in diabetic subjects who have had very disparate experi-ences of preceding glycaemia (Widom and Simonson, 1990; Amiel et al., 1991; Hvidberget al., 1996). The ability of the brain to adapt its metabolic and functional capacity accordingto previous glycaemic experience varies across different regions of the brain. Regions of thebrain that detect hypoglycaemia, and some parts of the cerebral cortex, may be able to adaptmore effectively to antecedent hypoglycaemia than other areas, to sustain glucose metabolismduring subsequent exposure. As blood glucose falls this would effectively destroy the normalprotective hierarchy of corrective and symptomatic responses that precede cognitive impair-ment, replacing it with the dangerous situation whereby cognitive impairment is the initialresponse to hypoglycaemia, with autonomic responses not occurring until the blood glucosedeclines to a much lower level. In this situation the patient becomes too confused and unableto recognise the warning symptoms and so take appropriate corrective action (Figure 8.3).Figure 8.3 The change in hierarchy of responses to hypoglycaemia (a) before and (b) after intensifiedinsulin therapy in type 1 diabetes mellitus
180 RISKS OF STRICT GLYCAEMIC CONTROLThe magnitude of the change in glycaemic thresholds for various functions of the brainin response to strict control of diabetes is variable. Where glucose thresholds for cognitivedysfunction do alter in people with impaired awareness of hypoglycaemia, the differencesbetween the blood glucose thresholds for the symptomatic and autonomic responses and thosefor the onset of cognitive impairment are much smaller. As a result, the window of opportu-nity for the patient to recognise that hypoglycaemia is developing is much narrower, givingless time for corrective action to be taken. As described above, the molecular mechanismscontrolling the thresholds for activation of the various components of the counterregulatoryresponses remain the subject of intense research.OTHER RISKS OF INTENSIFIED INSULIN THERAPYDiabetic Ketoacidosis and HyperinsulinaemiaAlthough severe hypoglycaemia was indisputably the major metabolic side-effect of intensiveinsulin therapy in the DCCT, concerns have been expressed that some intensive treatmentregimens may also increase the risk of developing ketosis. This was primarily related tothe use of CSII (with insulin pump therapy) and was thought to relate to the absence ofany intermediate-acting or background insulin in the event of pump failure. In insulin pumptherapy, soluble or fast-acting analogue insulin is delivered steadily by a slow infusion ofvery low doses throughout the day. The insulin delivery is accelerated before meals to deliverboluses, akin to giving intermittent subcutaneous injections of short-acting insulin. Becausethe basal insulin is delivered in a very low volume and there is no depot of intermediate-acting insulin in the subcutaneous tissues to act as a reservoir, an interruption in the deliveryof insulin can rapidly lead to hyperglycaemia and even ketosis, especially if the patient’sblood glucose is already elevated (Castilloa et al., 1996). This may occur as a result ofdisconnection of the pump, air in the delivery system, blockage in the tubing or morerarely, mechanical failure of the pump. The apparently high risk of diabetic ketoacidosis(DKA) with insulin pump therapy was first described when pumps left the experimentalcentres where they had been invented and were taken up for more general use (Knightet al., 1985), although the same centre that reported a problem with DKA also reportedsatisfactory experience overall with pump therapy (Knight et al., 1986). In 1997, a meta-analysis of trials of CSII has indicated that the rate of DKA was significantly higher (Eggeret al., 1997) and the rate of development of DKA was also slightly greater in intensively-treated patients in the DCCT, although many of those patients used multiple injectionsof insulin to improve their glycaemic control (The Diabetes Control and ComplicationsTrial Research Group, 1995b). However, a more recent meta-analysis, including studiesusing more modern equipment and up-dated algorithms for using pump therapy, is morereassuring (Pickup et al., 2002). Current intensive treatment regimens focus more on trans-ferring skills of flexible insulin dose adjustment more effectively to the patients and in thissetting, DKA rates are not higher. Indeed, experienced centres have utilised insulin pumptherapy to help people avoid recurrent DKA (Rodrigues et al., 2005). However, the riskis worth reiterating, as it can return when new technologies are applied in inexperiencedsettings.Intensive insulin therapy often leads to a redistribution of the times of administrationof insulin rather than a straightforward increase in dosage, and concerns have been raised
182 RISKS OF STRICT GLYCAEMIC CONTROLvery strict glycaemic control, and blood glucose targets may have to be higher when facedwith these problems. Frequent blood glucose monitoring is essential to identify biochemicalhypoglycaemia, and the use of basal-bolus insulin regimens (which predominantly use short-acting insulins) may be beneficial in avoiding recurrent hypoglycaemia. However, frequentblood glucose monitoring alone can sometimes exacerbate the problem, unless the patientis instructed in how to use the data to adjust insulin regimens prospectively to avoidproblems, rather than to react by immediate treatment of the inevitable occasional highreading. There have been few detailed behavioural studies in people with impaired awarenessof hypoglycaemia but it may be a particular problem where the links between high bloodglucose and risk of vascular complications have been very well accepted by the patient, whomay need convincing that transient hyperglycaemia is not a problem. Clinical experiencesuggests that many patients with such problems ‘glucose chase’, taking corrective actionwhenever they identify a high blood glucose concentration. Correcting this behaviour, inparticular avoiding postprandial glucose correction, and re-training patients to use glucosemonitoring to seek patterns for future dose adjustment, can be very beneficial. Programmesthat teach patients to test blood glucose before eating and to use the information to adjust thedose of insulin required for the immediate meal, allow people to live with greater flexibility.By recording the blood glucose results, recurrent patterns in changes can be sought againstwhich prospective adjustments to insulin regimens can be made. These measures allow HbA1cto be improved while lowering the risk of severe hypoglycaemia. It is important to recognisethat the preservation of physiological defences to hypoglycaemia is dependent upon theavoidance of hypoglycaemia in daily life, and not on tolerance of chronic hyperglycaemiaand an elevated glycated haemoglobin. As discussed above, the studies that have attempted torestore awareness of hypoglycaemia by avoidance of hypoglycaemia did not cause any majordeterioration of glycaemic control, although a modest increase in HbA1c of around 0.5–1.0%occurred in two studies (Fanelli et al., 1993; Dagogo-Jack et al., 1994). Anecdotally, averageblood glucose concentrations and HbA1c may even improve with strategies for avoidinghypoglycaemia, by preventing wide fluctuations in blood glucose.Strategies to avoid hypoglycaemia can be very time-consuming and labour-intensive, forthe patient as well as for the physician, and require several supportive measures, such ashaving to maintain daily telephone contact between the patient and the medical and nursingstaff (Fanelli et al., 1993). It took Cranston and colleagues (1994) up to 12 months for thesubjects taking part in their study to achieve three consecutive weeks when the home bloodglucose readings did not fall below 3.0 mmol/l. Two of three studies demonstrated partialrecovery of the counterregulatory responses to hypoglycaemia (Fanelli et al., 1993; Cranstonet al., 1994), but one did not (Dagogo-Jack et al., 1994), although the symptoms of hypo-glycaemia were restored. The number of subjects was small in all of these studies. However,the studies were often done in patients with an established problem of hypoglycaemia andnewer tools are at hand to help prevent or reverse the problems.Educational strategies cannot be emphasised too strongly. They remain to be testedspecifically in people who have major problems with recurrent severe hypoglycaemia buttheir ability to achieve better glycaemic control with less frequent hypoglycaemia is amajor improvement over the outcomes of the DCCT. For patients with type 1 diabetes,the introduction of fast-acting insulin analogues for insulin replacement at meal-times hasreduced hypoglycaemia, particularly at night, because of the much shorter duration of actionof fast-acting analogues (Brunelle et al., 1998; Home et al., 2000). Likewise, the longer-acting insulin analogues have been associated with a lower risk of nocturnal hypoglycaemia
PATIENTS UNSUITABLE FOR STRICT CONTROL 183(Pieber et al., 2000; Vague et al., 2003) and regimens that combine short and longer-actinginsulin analogues claim to have a lower risk of hypoglycaemia in patients with type 1 diabetes(Hermansen et al., 2004; Ashwell et al., 2005), although the methods of measurement ofhypoglycaemia in many of these trials was much less robust than was discussed earlier.The potential of CSII to reduce hypoglycaemia has also been highlighted. The use offaster and less painful glucose monitoring devices will facilitate home monitoring, althoughit remains critical that the data obtained are utilised through appropriate patient education.The advent of real-time glucose monitors may allow patients to avoid hypoglycaemia, as theycan take action to interrupt a steady decline in blood glucose concentration that they wouldnot previously have had the opportunity to observe. The value of these new technologiesremains to be proven in routine clinical use, but they do hold promise.The main defence against recurrent hypoglycaemia with its consequent blunting of subjec-tive symptomatic awareness remains the establishment of therapeutic goals that are realisticfor individual patients. The physician’s tendency to concentrate on eliminating hypergly-caemia has led to subnormal blood glucose values being ignored, a practice worsened by thebelief of some physicians and patients alike that, because an episode of biochemical hypo-glycaemia is asymptomatic, it is not important. There is no doubt that a clinically detectabledeterioration in performance of some aspects of cognitive function occurs in human subjectsat arterialised blood glucose concentrations of 3.0 mmol/l (see Chapter 2), and an absenceof symptoms at that level should ring alarm bells with the patient’s physician. Given thathealthy non-diabetic subjects do not commonly exhibit fasting blood glucose concentrationsbelow 4.0 mmol/l, it seems wholly unnecessary to encourage or even permit such subnor-mality in patients with diabetes (one exception to this maxim being pregnancy where healthynon-diabetic women do exhibit lower blood glucose levels as discussed in Chapter 10). Withintensive insulin therapy the therapeutic targets should be near-normal blood glucose levels(before meals 4.0–7.0 mmol/l, after meals 4.0–9.0 mmol/l, depending on time of testing),with a slightly higher than normal glucose at bedtime (7.0–9.0 mmol/l) to reduce the risk ofhypoglycaemia occurring during the night. Blood glucose measured during the night may bea little lower (≥ 3 6mmol/l), but in view of the evidence presented above, patients shouldavoid allowing it to fall any lower than this.PATIENTS UNSUITABLE FOR STRICT CONTROLThe DCCT demonstrated that any reduction in glycated haemoglobin is associated with areduced risk of microvascular complications over time, and the benefits are greater withhigher glycated haemoglobin concentrations (The Diabetes Control and Complications TrialResearch Group, 1996b). A cross-sectional study which suggested that the risk reductionfor nephropathy is near-maximal at a glycated haemoglobin of 8% (Krolewski et al., 1995)cannot be extrapolated to other microvascular complications, because in the DCCT noglycaemic threshold (estimated by glycated haemoglobin) for the development of retinopathywas demonstrated in a patient group whose average HbA1c was 7%. The long-term follow-up of the DCCT cohort has confirmed that intensive therapy benefits macrovascular aswell as microvascular risk and that its effects are sustained (Writing team for the DiabetesControl and Complications Trial/ Epidemiology of Diabetes Interventions and ComplicationsResearch Group, 2002). Thus, unless an individual already has normal glycated haemoglobinwith no problematical hypoglycaemia, no patient who has diabetes is unsuitable for attempts
184 RISKS OF STRICT GLYCAEMIC CONTROLto improve their glycaemic control, especially with modern techniques that are able to deliverimproved control without increasing hypoglycaemia risk.In practice, however, there are patients in whom attempts to achieve a near normal glycatedhaemoglobin are not appropriate (Box 8.2). Patients with advanced complications, especiallyretinopathy, have not been shown to benefit and a sudden improvement in glycaemic controlmay cause acceleration in severity of pre-proliferative or early proliferative retinopathy(Hanssen et al., 1986). Although some authorities claim that this should not be a contraindi-cation to improving glycaemic control (Chantelau and Kohner, 1997), as yet there is no realevidence for benefit in advanced cases and the retinopathy should be treated appropriatelybefore glycaemic control is intensified. Similarly, in patients with established renal impair-ment and severe macrovascular disease, attempts to treat elevated blood pressure and plasmalipids and to encourage patients to stop smoking may be more beneficial than targetingglycaemic control alone. As intensive insulin therapy is aimed at achieving benefit over aperiod of five to ten years or more, patients with a reduced life expectancy should not beexposed to the risks and rigours associated with this treatment regimen. This applies also toelderly patients, who may be frail and physically inactive.Very young patients may not be good candidates for very strict glycaemic control. Poorcontrol should not be encouraged in children, as growth may be jeopardised, and there issome evidence that pre-pubertal glycaemic control may influence the later risk of compli-cations (Donaghue et al., 1997; Holl et al., 1998). However, very small children, who arevery insulin-sensitive, may be at risk of intellectual damage if exposed to recurrent severehypoglycaemia (see Chapters 9 and 13).Box 8.2 Application of strict glycaemic control in type 1 diabetesCaution required:• Long duration of insulin-treated diabetes (counterregulatory deficiences).• Previous history of severe hypoglycaemia.• Established impaired awareness of hypoglycaemia.• History of epilepsy.• Patient unwilling to do home blood glucose monitoring.Contraindicated:• Extremes of age.• Ischaemic heart disease.• Unstable diabetic retinopathy (can be instituted after treatment).• Advanced diabetic complications.• Limited life expectancy (e.g. serious coexisting disease).
REFERENCES 185It is the patient who determines the degree of glycaemic control that they feel is worththe effort. Patients with very erratic life styles, and those who are not prepared to committhemselves to regular self-monitoring of blood glucose, with frequent attention to the timingof injection and adjustment of dosage of insulin, cannot safely undertake measures toachieve near-normoglycaemia. A compromise must be reached after a full discussion of therisks. Patients currently experiencing problematical hypoglycaemia may not wish to aim forglycaemic targets near the normal range, although the regimens of intensive insulin therapymay still be appropriate for them if they can eliminate hypoglycaemia from their daily lives.This may also be true of people undertaking dangerous or physically demanding jobs, whomay deliberately set higher blood glucose targets to protect against hypoglycaemia, but whoshould be encouraged to practice regular self-monitoring and adjustment of insulin doses. Itis the informed patient who must determine their own therapeutic aims at any given time.The doctor’s role is to try to ensure that the patient has the knowledge to make appropriatedecisions and to provide the tools to achieve these aims.CONCLUSIONS• The principal risks of intensive insulin therapy are hypoglycaemia and weight gain.• In earlier studies such as the DCCT, patients using intensive insulin regimens were threetimes more likely to have an episode of severe hypoglycaemia than those on conventionalinsulin regimens, but newer techniques for training patients to use insulin flexibly candeliver improved glycaemic control without any increase in severe hypoglycaemia, andsometimes with reduced hypoglycaemia occurrence.• It is likely that exposure to hypoglycaemia during intensive therapy impairs the counter-regulatory responses to hypoglycaemia and symptomatic awareness and this may be seenparticularly if glycated haemoglobin is within the non-diabetic range.• Total avoidance of hypoglycaemia can restore the symptomatic response to hypogly-caemia, but achieving this once problematic hypoglycaemia has been established may bedemanding and time-consuming, both for patients and healthcare professionals. Neverthe-less, the long-term benefits of good diabetic control in type 1 diabetes are unequivocaland current technologies should help more patients achieve it.• It is essential that all definitions of good glycaemic control include an absence of severehypoglycaemia as well as near-normal glycated haemoglobin. Intensified treatment regi-mens should be adjusted to incorporate both.REFERENCESAgardh CD, Eckert B, Agardh E (1992). Irreversible progression of severe retinopathy in young type-1insulin-dependent diabetes mellitus patients after improved metabolic control. Journal of DiabeticComplications 6: 96–100.Amiel SA, Tamborlane WV, Simonson DC, Sherwin RS (1987). Defective glucose counterregula-tion after strict glycemic control of insulin-dependent diabetes mellitus. New England Journal ofMedicine 316: 1376–83.
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188 RISKS OF STRICT GLYCAEMIC CONTROLKorzon-Burakowska A, Hopkins D, Matyka K, Lomas J, Pernet A, Macdonald I, Amiel S (1998).Effects of glycemic control on protective responses against hypoglycemia in type 2 diabetes.Diabetes Care 21: 283–90.Krolewski AS, Laffel LM, Krolewski M, Quinn M, Warram JH (1995). Glycosylated hemoglobinand the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus. New EnglandJournal of Medicine 332: 1251–5.Lassmann-Vague V, Belicar P, Alessis C, Raccah D, Vialettes B, Vague P (1996). Insulin kinetics intype I diabetic patients treated by continuous intraperitoneal insulin infusion: influence of anti-insulinantibodies. Diabetic Medicine 13: 1051–5.Limbert C, Schwingshandl J, Haas J, Roth R, Borkenstein M (1993). Severe hypoglycemia in childrenand adolescents with IDDM: frequency and associated factors. Journal of Diabetes Complications7: 216–20.Liu D, McManus RM, Ryan EA (1996). Improved counter-regulatory hormonal and symptomaticresponses to hypoglycemia in patients with insulin-dependent diabetes mellitus after 3 months ofless strict glycemic control. Clinical and Investigative Medicine 19: 71–82.Maran A, Lomas J, Macdonald IA, Amiel SA (1995). Lack of preservation of higher brain functionduring hypoglycaemia in patients with intensively-treated IDDM. Diabetologia 38: 1412–18.Muhlhauser I, Overmann H, Bender R, Bott U, Berger M (1998). Risk factors of severe hypoglycaemia inadult patients with type I diabetes – a prospective population based study. Diabetologia 41: 1274–82.Nathan DM, Lachin J, Cleary P, Orchard T, Brillon DJ, Backlund JY et al. (2003). Intensive diabetestherapy and carotid intima-media thickness in type 1 diabetes mellitus. New England Journal ofMedicine 348: 2294–303.Pampanelli S, Fanelli C, Lalli C, Gofetta M, Del Sindaco P, Lepore M et al. (1996). Long-termintensive therapy in IDDM: effects on HbA1c, risk for severe and mild hypoglycaemia, status ofcounterregulation and awareness of hypoglycaemia. Diabetologia 39: 677–86.Pedersen-Bjergaard U, Agerholm-Larsen B, Pramming S, Hougaard P, Thorsteinsson B (2003). Predic-tion of severe hypoglycaemia by angiotensin-converting enzyme activity and genotype in type 1diabetes. Diabetologia 46: 89–96.Pickup J, Mattock M, Kerry S (2002). Glycaemic control with continuous subcutaneous insulininfusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysisof randomised controlled trials. British Medical Journal 324: 705–8.Pieber TR, Eugene-Jolchine I, Derobert E (2000). Efficacy and safety of HOE 901 versus NPH insulinin patients with type 1 diabetes. The European Study Group of HOE 901 in type 1 diabetes. DiabetesCare 23: 157–62.Plank J, Kohler G, Rakovac I, Semlitsch BM, Horvath K, Bock G et al. (2004). Long-term evaluationof a structured outpatient education programme for intensified insulin therapy in patients with type1 diabetes: a 12-year follow-up. Diabetologia 47: 1370–75.Rodrigues I, Reid HA, Ismail K, Amiel SA (2005). Indications and efficacy of continuous subcutaneousinsulin infusion (CSII) therapy in type 1 diabetes mellitus: a clinical audit in a specialist service.Diabetic Medicine: 22: 842–9.Ryder RE, Owens DR, Hayes TM, Ghatei MA, Bloom SR (1990). Unawareness of hypoglycaemia andinadequate hypoglycaemic counterregulation: no causal relation with diabetic autonomic neuropathy.British Medical Journal 301: 783–7.Samann A, Muhlhauser I, Bender R, Kloos C, Muller UA (2005). Glycaemic control and severehypoglycaemia following training in flexible, intensive insulin therapy to enable dietary freedom inpeople with type 1 diabetes: a prospective implementation study. Diabetologia 48: 1965–70.Segal SA, Fanelli CG, Dence CS, Markham J, Videen TO, Paramore DS et al. (2001). Blood-to-brainglucose transport, cerebral glucose metabolism, and cerebral blood flow are not increased afterhypoglycemia. Diabetes 50: 1911–7.Shah SC, Malone JL, Simpson NE (1989). A randomized trial of intensive insulin therapy in newlydiagnosed insulin-dependent diabetes mellitus. New England Journal of Medicine 320: 550–4.
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192 HYPOGLYCAEMIA IN CHILDREN WITH DIABETESsize, from premature infants to adult life (Bier et al., 1977). There is a marked changein the correlation between body weight and hepatic glucose production corresponding tomid-puberty (approximately 40 kg) indicating that brain growth is virtually complete (Bieret al., 1977). However, the developing brain also has the ability to use alternative substratesfor cerebral metabolism, and during fasting young children have higher concentrations ofketones and lactate when compared to adults (Haymond et al., 1982).A number of studies have examined metabolic parameters, including blood glucoseconcentrations, following fasts of varying duration in children. On the whole these studieshave been used to provide normative data for use in the clinical evaluation of children withpotential disorders of metabolism; as a result the fasts have been prolonged and samplinginfrequent. There is little detailed information on metabolic variables during a short fast asis experienced by children with diabetes, for example when they go to sleep. One study ofnocturnal glucose homeostasis in 39 children, subsequently found to have a constitutionalshort stature, demonstrated a cyclical variation in blood glucose concentrations during thenight with a periodicity of 80–120 minutes (Stirling et al., 1991). At some stage of thenight blood glucose levels fell transiently to below 3 mmol/l in 5% of the children, but it isdifficult to know if these children are representative of those who grow normally.Other studies have examined glucose and metabolite profiles intermittently duringprolonged fasts of 24–36 hour duration (Chaussain, 1973; Chaussain et al., 1974; Chaussainet al., 1977; Saudubray et al., 1981; Haymond et al., 1982; Kerr et al., 1983; Lamerset al., 1985a; Lamers et al., 1985b). Fasting glucose concentrations varied depending on theduration of the fast and age of child studied. After 24 hours, blood glucose was found torange from 3.0–3.5 mmol/l. Some of these studies suggested a positive correlation betweenfasting blood glucose concentrations and age (Chaussain et al., 1977; Saudubray et al., 1981;Lamers et al., 1985a).Definition of Hypoglycaemia in Childhood DiabetesAlthough there has been great controversy regarding the biochemical definition of hypogly-caemia for the diagnosis of pathological states in the paediatric population (Koh et al., 1988),these arguments should not apply to type 1 diabetes. The management of type 1 diabetesinvolves striving towards the maintenance of glucose concentrations well within the physio-logical range rather than merely outside of the pathological range. The only study from thosediscussed above to examine glucose concentrations after a duration of fasting that wouldrepresent that occurring as part of normal daily living (14 hours) found a fasting glucoseconcentration of 4 3 ± 0 1mmol/l in children aged 3–15 years old (Lamers et al., 1985b).Guidelines now suggest that diabetes management should aim to keep plasma glucose above4 mmol/l (‘four should be the floor’ was recommended in a Diabetes UK report in 1996),and this is probably a reasonable recommendation for children.Both in research studies and in clinical care, hypoglycaemia is often subdivided intodegrees of severity based on the intervention required. An example of such a classificationthat was suggested by the International Society for Paediatric and Adolescent Diabetologists(ISPAD) is shown in Table 9.1. It should be noted that the usual adult definition of ‘mild’(i.e., self-treated) hypoglycaemia cannot be applied in young children who rely on theiradult carers for their diabetes management, because they are unlikely to be able to treat theepisodes themselves.
SIGNS AND SYMPTOMS OF HYPOGLYCAEMIA 193Table 9.1 Example of classification of hypoglycaemia (data sourced from ISPAD Consensus Guide-lines, 2000)Grade DescriptionMild (Grade 1) Aware of, responds to and self-treats the hypoglycaemiaModerate (Grade 2) Cannot respond to hypoglycaemia and requires help fromsomeone else, but oral treatment is successfulSevere (Grade 3) Semi-conscious or unconscious or in coma ± convulsions andmay require parenteral therapy (glucagon or IV glucose)PREVALENCE OF HYPOGLYCAEMIAAs the definition of hypoglycaemia has been controversial, studies of prevalence have oftenused variable definitions, both for daytime hypoglycaemia and for that occurring duringsleep. Hypoglycaemia is notoriously under-reported, as episodes, particularly mild ones, arequickly forgotten. Even severe episodes may be overlooked. The individual themselves mayhave amnesia for the event and, if it occurred away from their normal environment, nobodymay document what took place.A number of studies have examined the prevalence of severe hypoglycaemia in thepaediatric population (Table 9.2). Some studies included only episodes of coma/convulsionwhereas others also included those events in which neurological impairment was severeenough to require intervention. Hypoglycaemia has been shown to be a significant problembut, given the methodological complexities, prevalence rates of severe hypoglycaemia havevaried greatly from 3.1 to 85.7 episodes per 100 patient-years. It is likely that less severeepisodes are much more common and under-reported.Nocturnal HypoglycaemiaStudies have also examined the prevalence of nocturnal hypoglycaemia. In these studiesa biochemical rather than a symptomatic definition of hypoglycaemia was used and hasbeen very variable, ranging from 3.0 to 3.8 mmol/l. The prevalence of hypoglycaemia hasvaried from 10 to 55% but it is noticeable that the more recent studies have detecteda higher prevalence (Beregszaszi et al., 1997; Lopez et al., 1997; Porter et al., 1997;Matyka et al., 1999a). The majority of these episodes do not wake the patient and, ineveryday life, a great number of episodes of nocturnal hypoglycaemia will be completelyundetected.SIGNS AND SYMPTOMS OF HYPOGLYCAEMIADaytime HypoglycaemiaThe classical symptoms of hypoglycaemia, as described in adults (Chapter 2), are classi-fied into three distinct groups: autonomic, neuroglycopenic and non-specific (Deary et al.,1993). In adults the sympathoadrenal response during hypoglycaemia is primarily respon-sible for the classical autonomic symptoms which alert the individual to the falling glucose
196 HYPOGLYCAEMIA IN CHILDREN WITH DIABETESconcentration so that corrective action can be taken. The classical autonomic symptomsoccur in adults between 3.0 and 3.6 mmol/l and include: sweating, palpitations, hunger andshaking. If glucose concentrations fall further, neuroglycopenia will develop, usually at aglucose concentration around 2.8 mmol/l, and if it falls further the individual may not be ableto correct the hypoglycaemia themselves. The most common neuroglycopenic symptomsare: confusion, drowsiness, odd behaviour, speech difficulty and incoordination. If bloodglucose continues to fall, coma or convulsion could ensue although the glycaemic thresholdat which this occurs is not certain.The symptoms of hypoglycaemia in childhood differ from adults. In one study, childrenand parents were asked which symptoms and signs alerted them to an episode of hypogly-caemia (McCrimmon et al., 1995). The authors reported that symptoms did not separate intodistinct autonomic and neuroglycopenic categories and behavioural symptoms were promi-nent. Another study examined the frequency of hypoglycaemia in a group of children andadolescents using a three-month diary (Tupola et al., 1998a). Episodes of hypoglycaemia(defined as a blood glucose ≤ 3mmol/l) were documented along with symptoms. Of thepatients (aged 2.5–21 years), 52% had a total of 287 episodes of hypoglycaemia, the majorityof which (77%) were mild. The most common presenting symptoms were weakness, tremor,hunger and drowsiness; 39% of symptoms were classified as ‘adrenergic’ (autonomic) and61% as neuroglycopenic or non-specific behavioural (Table 9.3). The dominant symptomswere different in different age groups of children. Those children less than six years ofage had fewer autonomic symptoms than adolescents, with the commonest symptom beingdrowsiness in young children and tremor in the older children (Tupola et al., 1998a).Nocturnal HypoglycaemiaThe majority of episodes of nocturnal hypoglycaemia do not awaken the child from sleepand thus go undetected, even in those who have normal awareness of hypoglycaemiaduring waking hours (Gale and Tattersall, 1979; Bendtson et al., 1993; Porter et al., 1996;Table 9.3 Reported symptoms during 221 episodes of mild hypoglycaemia(data sourced from Tupola et al., 1998b)Symptom Prevalence (%)autonomic tremor 22hunger 14sweating 4neuroglycopenic drowsiness 34irritability/aggressiveness 4dizziness 1poor concentration 1blurred vision 1non-specific weakness 7nausea 7abdominal pain 2headache 2tearfulness 1
RISK FACTORS FOR HYPOGLYCAEMIA 197Beregszaszi et al., 1997; Lopez et al., 1997; Matyka et al., 1999a). The reasons for thislack of awareness of nocturnal episodes of hypoglycaemia are unclear, but are discussedin Chapter 4. As symptom generation depends on intact autonomic and counterregulatorydefence mechanisms, it has been postulated that diminished counterregulation overnight mayresult in lack of arousal when hypoglycaemia occurs during sleep (Bendtson et al., 1993;Jones et al., 1998).RISK FACTORS FOR HYPOGLYCAEMIAThe discussion of risk factors naturally overlaps with that of prevention of hypoglycaemia,and a fuller review of specific interventions is provided in the section entitled ‘Prevention’ onpage 207. Table 9.3 presents the results of studies that have been performed to examine theprevalence of severe hypoglycaemia in childhood since the Diabetes Control and Complica-tions Trial (DCCT) was published (The Diabetes Control and Complications Trial ResearchGroup, 1993). Although a number of studies have suggested correlations between youngerage and strict glycaemic control, it is important to note that many individual episodes ofhypoglycaemia may be explained by missed meals or unplanned exercise, but this wouldnot have been addressed in epidemiological studies.Glycaemic ControlInsulin requirements vary with age and are approximately 0.5–1 U/kg/day before puberty and1.5–2 U/kg/day during adolescence, reflecting the insulin resistance that is present during thisperiod of rapid growth and development (Dunger, 1992). Despite numerous developmentsin terms of novel insulin preparations and modes of delivery, people with type 1 diabetesstill experience varying states of insulin deficiency or excess that are difficult to controland predict. This is probably most evident in adolescents with type 1 diabetes in whomperipheral hyperinsulinaemia is achieved in an attempt to replace adequate levels of insulinin the portal circulation during the pubertal growth spurt (Dunger, 1992).The DCCT highlighted the dilemma faced by all patients with type 1 diabetes (TheDiabetes Control and Complications Trial Research Group, 1993). Attempts at improvingglycaemic control, by intensifying diabetes management, in an effort to decrease the likeli-hood of the long-term microvascular complications of diabetes led to a significant increasein the risk of severe hypoglycaemia (SH). In the DCCT, subjects in the intensified treatmentgroup had a three-fold higher risk of SH (The Diabetes Control and Complications TrialResearch Group, 1993). A group of 195 adolescents, aged between 13 and 17 years, took partin this trial (The Diabetes Control and Complications Trial Research Group, 1994). Althoughthe benefits of improved glycaemic control in terms of microvascular complications werestill significant, the adolescents found it more difficult to achieve the low HbA1c concen-tration than adults (8 06 ± 0 13 versus 7 12 ± 0 03%; p < 0 001). Despite this, adolescentshad a greater tendency towards experiencing severe hypoglycaemia: 85.7 events per 100patient-years versus 56.9 events in the adult cohort (The Diabetes Control and Complica-tions Trial Research Group, 1994). However, in a European-wide clinical audit, which wasdesigned to look at metabolic control in children and adolescents, it was found that severehypoglycaemia was as common in those centres where metabolic control was poor, as in
198 HYPOGLYCAEMIA IN CHILDREN WITH DIABETESWe do not have rights to reproduce thisfigure electronicallyFigure 9.1 Rates of (a) Severe hypoglycaemia, and (b) average HbA1c by calender year. Reproducedfrom Bulsara et al. (2004) with permission from The American Diabetes Associationhypoglycaemia was as common in those centres where metabolic control was poor, as inthose centres that achieved better control as judged by HbA1c, suggesting that research doesnot always reflect clinical experience (Mortensen et al., 1997).Since 1993, ample opportunity has been present to refine the approaches to intensiveinsulin therapy and to improve education both for patients and physicians. Longitudinalstudies of the incidence of hypoglycaemia are unusual but one audit study from a largepaediatric clinic in Western Australia demonstrated an interesting trend in incidence of SHover a period of ten years (Bulsara et al., 2004). Over the first five years of the study,the incidence increased by 29% in conjunction with a decline in the average HbA1c ofabout 0.2% per year. Despite a continued improvement in glycaemic control, the inci-dence of SH appeared to plateau at this clinical centre suggesting that improved diabetesmanagement, from more effective insulin regimens or better education, can improve bloodglucose concentrations without a concomitant increase in incidence of hypoglycaemia(Figure 9.1).Nocturnal Insulin RequirementsThe mismatch of insulin delivery and insulin requirements on standard insulin regimensis particularly evident during the night and most episodes of severe hypoglycaemia occurduring sleep (Edge et al., 1990a; The Diabetes Control and Complications Trial ResearchGroup, 1997). Current insulin replacement regimens tend to result in hyperinsulinaemia inthe early part of the night, although physiological insulin requirement is at its nadir between24:00–03:00 hours, and so exacerbates the risk of hypoglycaemia at this time (Matykaet al., 1999a; Mohn et al., 1999; Ford-Adams et al., 2003). Insulin requirements then peakbetween 04:00–08:00 hours and a ‘dawn phenomenon’ occurs which can lead to fastinghyperglycaemia (Bolli and Gerich, 1984; Edge et al., 1990b) and is thought to result fromGH secretion during the later part of the night (De Feo et al., 1990; Edge et al., 1990b)
RISK FACTORS FOR HYPOGLYCAEMIA 199exacerbated further by the delayed effects of daytime physical activity on muscle glucosemetabolism and the prolonged period of fasting that occurs overnight, especially in youngchildren. This suggests that the overnight period is the time of greatest hypoglycaemia risk(The Diabetes Control and Complications Trial Research Group, 1997).Intensive Insulin RegimensFew studies have examined the impact of insulin regimen on the risk of hypoglycaemiain children. The DCCT did find a significantly higher risk of hypoglycaemia among the195 adolescents who participated in the study although this was a comparison of overallglycaemic control and not of specific regimens (The Diabetes Control and ComplicationsTrial Research Group, 1994). A number of studies examining prevalence of hypoglycaemiahave found an inverse correlation between hypoglycaemia risk and glycated haemoglobin(Table 9.2). The Hvidore Study Group has formed a collaboration between 21 internationalpaediatric centres from 18 countries (Holl et al., 2003). The group surveyed paediatricdiabetes management of 2873 children aged up to 18 years in 1995 and restudied 872 ofthese children in 1998. Although the use of multiple injection regimens increased from 42%to 71% this did not lead to an improvement in glycaemic control as judged by glycatedhaemoglobin concentrations. Although there was a tendency towards an increase in thefrequency of severe hypoglycaemia in the group of children/adolescents who had had anintensification of insulin regimen, this did not reach statistical significance, perhaps becauseof the low number of events recorded (Holl et al., 2003).Another study of more than 6000 children has suggested that injection regimen and centreexperience, as judged by the size of the clinic, may be significant risk factors for severehypoglycaemia (Wagner et al., 2005). In this study of children aged up to nine years, anincreased risk of hypoglycaemia was observed in those children taking four insulin injectionsdaily or on insulin pump therapy, compared to those children taking one to three injectionsdaily.It is important to note that even the more recent studies do not include data acquired sincethe introduction of the insulin analogues or the use of more physiological and intensiveinsulin regimens. Small studies of a few children in which insulin analogues have beencompared with human insulins suggest that the risk of hypoglycaemia may be lower withanalogues without compromising glycaemic control (see later section on hypoglycaemiaprevention on page 209).DietChildren with type 1 diabetes have the same nutritional requirements as children withoutdiabetes. However, meals and snacks containing a high proportion of carbohydrate, have tobe regularly distributed throughout the day to avoid the extremes of hypo- and hypergly-caemia (Magrath et al., 1993). This can be an issue for children who do not want to bedifferent from their peers and do not want to eat at times when there friends are playing.Toddlers can present a special problem as many do not eat regular meals but graze duringthe day.Surprisingly, there has been little systematic study of the role of both quantity andquality of dietary components on the risk of hypoglycaemia. However, some studies of the
200 HYPOGLYCAEMIA IN CHILDREN WITH DIABETESprevalence of hypoglycaemia have found that a number of episodes can be attributed tomissed meals (Daneman et al., 1989; Davis et al., 1997; Tupola et al., 1998b). The impactof dietary interventions in the avoidance of hypoglycaemia, mainly during sleep, have beenexamined, and this is discussed later in the section on hypoglycaemia prevention.Physical ActivityAs early as 1926, it was found that exercise could potentiate the hypoglycaemic effect ofinsulin in patients with type 1 diabetes (Lawrence, 1926). During the first 5–10 minutes ofexercising, muscle glycogen is used as the primary source of energy (Price et al., 1994).Subsequently, fuel is provided increasingly by circulating glucose, through gluconeogenesisand free fatty acids (FFAs), the release of which are under hormonal control and dependentpredominantly on the portal glucagon : insulin ratio (Ahlborg et al., 1974). The acute effectsof exercise are followed by restoration of the metabolic milieu. Muscle glucose uptakeremains elevated as glycogen stores are replenished and although insulin sensitivity isenhanced in the period after exercise, increased glucose uptake by skeletal muscle can occureven in the absence of insulin (Cartee and Holloszy, 1990). The time taken to restore muscleglycogen to pre-exercise levels will depend on the intensity and duration of the exerciseperformed, and the timing and amount of dietary carbohydrate intake, but it can take severalhours – typically 6–20 hours (Ivy and Holloszy, 1981; Richter, 1996).Until recently there has been little systematic study of the impact of exercise in childhoodon glucose homeostasis. One study used continuous glucose monitoring to study a stan-dardised exercise protocol in a group of children who were using continuous subcutaneousinsulin infusion (CSII). Glucose profiles were examined both during and after exercise ona cycle ergometer with the infusion pump either switched on or off (Admon et al., 2005).Hypoglycaemia was more common after exercise than during it, and this was true whetherCSII was on or off. All subjects had one to three episodes of symptomatic hypoglycaemiawithin 2.5 to 12 hours after exercise and four subjects had asymptomatic hypoglycaemiaduring exercise, only one of whom had consumed extra carbohydrate because their pre-exercise blood glucose had been below 5.5 mmol/l. Another study examined the impact ofdaytime exercise on overnight blood glucose profiles in 50 subjects aged 10–18 years onintensive insulin regimens (Tsalikian et al., 2005). On one occasion they were studied duringa day of afternoon exercise, involving four periods of 15 minutes each on a treadmill at aheart rate estimated to be 55% of maximum effort for this age group, and on a separateoccasion during a rest day. In this study, 22% of subjects developed hypoglycaemia duringexercise; overnight hypoglycaemia was more common during the night after the afternoonexercise than during a night after the rest day (Tsalikian et al., 2005).AgeStudies of prevalence of hypoglycaemia have consistently found that younger children,especially those under the age of five years, are at increased risk of hypoglycaemia. Thismay be a consequence of increased insulin sensitivity, irregular eating patterns or impairedsymptomatic awareness.
COUNTERREGULATION IN CHILDHOOD 201GeneticsRecent studies suggest that molecular markers may influence hypoglycaemia risk. A poly-morphism in the gene encoding for angiotensin converting enzyme (ACE) has been describedindicating the presence (insertion, I) or absence (deletion, D) of a 287 base pair sequencewithin intron 16 resulting in three genotypes: II, ID and DD. These genotypes are stronglyrelated to serum ACE concentration with the highest values in DD and the lowest valuesin II genotypes (Rigat et al., 1990). Danish studies of adults with type 1 diabetes observedthat patients with an II (insertion) genotype, who had a low serum ACE activity, had asignificantly lower frequency of severe hypoglycaemia (Pedersen-Bjergaard et al., 2001;Pedersen-Bjergaard et al., 2003). A Swedish study of children with type 1 diabetes hasreported a six-fold lower frequency of severe hypoglycaemia in those patients who had lowserum ACE activity (Nordfelt and Samuelsson, 2003). However, a study of 585 children andadolescents in an Australian centre has not confirmed this association (Bulsara et al., 2007),so this remains controversial.Clinic ExperienceRecent therapeutic developments, with the availability of novel insulin analogues and thegreater use of intensive insulin regimens, have required re-education not only of patientsbut also the multidisciplinary team. Few studies have examined the impact of the clinicstructure on risk of hypoglycaemia. One large multicentre study in Germany did show alink between small clinic size (< 50 children) and an increased risk of severe hypogly-caemia (Wagner et al., 2005). Another longitudinal study of prevalence of severe hypo-glycaemia in Australia showed an increase in hypoglycaemia risk as the mean glycatedhaemoglobin in the clinic declined. However, over the final five years of the study the riskof hypoglycaemia plateaued while the HbA1c continued to decrease, suggesting the possiblebenefit of familiarity among patients, healthcare professionals or both (Bulsara et al., 2004)(Figure 9.1).COUNTERREGULATION IN CHILDHOODThe physiology of counterregulation is the subject of Chapters 1 and 6, but a brief overviewof studies of counterregulation in childhood will be presented here. Despite the ethical andpractical problems of inducing hypoglycaemia in children for research purposes, a numberof studies have been performed (Amiel et al., 1987; Brambilla et al., 1987; Singer-Granicket al., 1988; Hoffman et al., 1991; Jones et al., 1991; Bjorgaas et al., 1997a; Ross et al.,2005). These studies have all examined experimentally-induced hypoglycaemia, either usingan insulin infusion method or a hyperinsulinaemic, hypoglycaemic glucose clamp technique.The results of individual hormonal responses are discussed briefly.GlucagonAs in adults the glucagon response during hypoglycaemia is lost in children with diabetes(Amiel et al., 1987; Jones et al., 1991; Ross et al., 2005). This is also the case in toddlers,
202 HYPOGLYCAEMIA IN CHILDREN WITH DIABETESaged 18–57 months old, who have a very short duration of diabetes (Brambilla et al., 1987).This means that individuals with diabetes are more reliant on adequate epinephrine responsesto correct hypoglycaemia.EpinephrineThe majority of studies suggest that children have exaggerated epinephrine responses tohypoglycaemia, with peak values that are two-fold higher than those found in adults (Amielet al., 1987). Data from prepubertal children have been analysed separately from pubertalchildren and no significant differences were found in epinephrine responses (Amiel et al.,1987; Ross et al., 2005). One study, using an insulin infusion as opposed to a hyper-insulinaemic clamp, did suggest that epinephrine responses were blunted in a group ofpoorly-controlled adolescents (Bjorgaas et al., 1997a). The reason for the discrepancy inresults is not clear.Glucose thresholds for counterregulatory responses have received very little attention.In a study of poorly-controlled adolescents (average total HbA1: 15%) glucose thresholdsfor epinephrine secretion were significantly higher, with the poorly-controlled adolescentsreleasing epinephrine at a glucose concentration of 4.7 mmol/l compared to 3.9 mmol/l inhealthy adolescents (Jones et al., 1991).Growth HormoneNone of the reported studies have identified defects in GH release during hypoglycaemia.Generally GH has been found to increase in response to hypoglycaemia both in childrenwith diabetes and in non-diabetic controls (Amiel et al., 1987; Brambilla et al., 1987; Joneset al., 1991).CortisolCortisol, like growth hormone, becomes more important as hypoglycaemia becomesprolonged. Studies of hypoglycaemia in children have shown variable results. Brambillafound no increase in cortisol in either the diabetic or control group of toddlers studied(Brambilla et al., 1987), whereas others have documented an increase in cortisol both inchildren with and without diabetes (Amiel et al., 1987; Jones et al., 1991).Effect of Sleep Stage on CounterregulationOne study of nocturnal hypoglycaemia in prepubertal children on conventional insulinregimens, found that the median glucose nadir during episodes of nocturnal hypoglycaemiawas 1.9 mmol/l (range: 1.1–3.3 mmol/l) and the median duration was 270 minutes (range:30–630 minutes) (Matyka et al., 1999a). This is similar to adults in whom the averageduration of hypoglycaemia (glucose below 2 mmol/l) during the night was found to be threehours in a group of adults with poorly-controlled diabetes (Gale and Tattersall, 1979).Conventional wisdom would argue that prolonged episodes of hypoglycaemia are unusualas hypoglycaemia is promptly corrected by counterregulatory defence mechanisms. However,
CONSEQUENCES OF HYPOGLYCAEMIA 203studies of nocturnal hypoglycaemia suggest that counterregulatory responses may be bluntedduring sleep (see Chapter 4). A study of spontaneous nocturnal hypoglycaemia in prepu-bertal children with diabetes demonstrated blunted and delayed counterregulatory hormoneresponses during sleep (Matyka et al., 1999b). Peak epinephrine response was only 0.9 nmol/land there was a marked delay between the glucose falling below 3.5 mmol/l and a significantrise in epinephrine; the mean delay was 170 minutes. Another study examined counterreg-ulatory hormone responses during hypoglycaemia that was experimentally-induced duringthe time of night when slow wave sleep predominates, and these responses were comparedwith those to hypoglycaemia induced during the day with the subjects awake and then againwhen they were awake during the night (Jones et al., 1998). Adolescents with diabetesand healthy controls participated in the study. Epinephrine responses during hypoglycaemiawere blunted when hypoglycaemia was induced during slow wave sleep compared to whenhypoglycaemia was induced when subjects were awake during the day or during the night(Jones et al., 1998). Studies of the physiology of sleep have demonstrated both variationsin autonomic tone and cerebral glucose metabolism going from slow wave sleep through torapid eye movement sleep which may influence the counterregulatory response during sleep(Maquet et al., 1990; Parmeggiani and Morrison, 1990).CONSEQUENCES OF HYPOGLYCAEMIACognitive ImpairmentSevere hypoglycaemia can cause catastrophic cerebral damage when it is profound andprolonged, and in very young children this may be a risk associated with a variety of causes(Lucas et al., 1988). Glucose is critical not only as the major fuel for cerebral metabolism butalso as a precursor of essential substrates which are essential for normal brain development(Glazer and Weber, 1971). Concerns have been raised that recurrent hypoglycaemia couldaffect long-term academic achievement in children with type 1 diabetes, from the effectsof hypoglycaemia disrupting school performance to the possibility of damage accumulatingover time.Acute effectsFew studies have studied the impact of acute hypoglycaemia on cognitive performance in chil-dren or adolescents. One study of the effects of experimentally-induced mild hypoglycaemia(3.1–3.6 mmol/l) found decrements in tests of mental flexibility and on measures that requiredplanning and decision making and a rapid response, although the results were variable withinsubjects (Ryan et al., 1990). The learning ability of children, who spend much of their day atschool assimilating information, could be seriously compromised if they experience frequentepisodes of even mild hypoglycaemia during their time in class. Children can also be affectedif they miss lessons because of severe hypoglycaemic events and could be compromised byasymptomatic episodes of hypoglycaemia that go undetected and therefore untreated. Thereis some evidence to suggest that children may be particularly susceptible to mild episodes ofhypoglycaemia – studies examining P300 evoked potentials and EEG changes in response to
204 HYPOGLYCAEMIA IN CHILDREN WITH DIABETEShypoglycaemia have found that abnormalities commence at a higher blood glucose level inchildren than in adults (Jones et al., 1995; Bjorgaas et al., 1998).The effect of nocturnal hypoglycaemia on cognitive function has received little attention.Cognitive performance could be directly affected by hypoglycaemia, but also by sleepdisturbance. The few studies of nocturnal hypoglycaemia in children and adolescents withtype 1 diabetes have shown no deleterious effect on overall sleep physiology (Bendtsonet al., 1992; Porter et al., 1996; Matyka et al. 2000, Pillar et al., 2003) or on cognitivefunction the following morning.Long-term effectsEarly studies of children with diabetes suggested that they were ‘mentally superior’ (Westet al., 1934). However, in recent years concern has been expressed about the potential impactof recurrent episodes of hypoglycaemia on intellectual performance. It is beyond the scopeof this chapter to provide a comprehensive review on this topic and only more recent studiesare reviewed.The developing brain is extremely vulnerable to all types of cerebral trauma. Studies ofchildren who have experienced closed head injuries suggest that the consequences may bedelayed, with subtle cerebral damage becoming evident with time as normal developmentalmilestones are delayed. A large number of studies have examined the impact of recurrenthypoglycaemia in childhood (Ryan et al., 1985; Golden et al., 1989; Bjorgaas et al., 1997b;Hershey et al., 1999; Rovet and Ehrlich, 1999; Northam et al., 2001; Wysocki et al.,2003). Almost without exception, the results have shown a possible link between severehypoglycaemia and decrements in cognitive performance and that those children most atrisk of cognitive impairment have been those diagnosed early in life – usually less than fiveyears of age (Ryan et al., 1985; Golden et al., 1989; Bjorgaas et al., 1997b; Northam et al.,2001). Deficiencies have been found in several cognitive domains but are more likely inthose originating in the frontal lobe. One of the most impressive longitudinal studies hasbeen that of Northam and colleagues. Cognitive performance was assessed in a large groupof children (123 at baseline) with newly-diagnosed diabetes, aged 3–14 years, who werecompared to healthy controls at three months, two years and six years following diagnosis(Northam et al., 2001). At six years, children with diabetes performed more poorly inmeasures of intelligence, attention, processing speed, long-term memory and executive skills.Attention, processing speed and executive skills were especially affected in those childrenwho had developed diabetes when less than four years of age (Northam et al., 2001). Severehypoglycaemia was associated with lower verbal and full-scale intelligence quotient (IQ)scores. The authors concluded that recurrent hypoglycaemia was a potential explanation forthese cognitive deficits but could not exclude an effect of chronic hyperglycaemia.Another study has performed a cognitive test battery and structural neuroimaging usingMagnetic Resonance Imaging in a group of young adults with type 1 diabetes and comparedthe findings between those with either early onset disease, defined as less than sevenyears, and late onset disease (Ferguson et al., 2005). Physiological risk variables such asdiabetes duration, evidence of microvascular disease and retrospective reporting of precedingexposure to severe hypoglycaemia were also assessed. The patients with early onset diabeteswere found to have deficits in non-verbal intelligence, information processing ability andpsychomotor speed. The authors also found higher ventricular volumes and higher frequency
CONSEQUENCES OF HYPOGLYCAEMIA 205of mild ventricular atrophy in those with early onset diabetes. None of the findings wererelated to the presence of microvascular disease or diabetes duration, suggesting that thecumulative effects of hyperglycaemia were unlikely to be causative. However, no definite linkwas confirmed between exposure to severe hypoglycaemia and any of these defects, althoughthe study was limited by retrospective reporting of the history of preceding hypoglycaemiaover a long period of time (Ferguson et al., 2005). Another study did not find a differencein tests of cognitive function over a period of 18 months in 142 patients taking part in astudy examining the impact of intensive therapy versus usual care (Wysocki et al., 2003).The study group had a wide age range from 6–15 years and data from younger childrenwere not analysed separately.Although there are methodological problems in designing studies to assess long-termcognitive function in children who have an ongoing chronic disorder, these studies do raiseanxieties. It is felt that until hypoglycaemia can be reliably avoided, glycaemic control shouldbe less intensively managed in younger children to avoid the risk of severe hypoglycaemia.This would put younger children at greater risk of developing the long-term microvascularcomplications of diabetes in an attempt to avoid the possible cognitive defects that may beassociated with recurrent hypoglycaemia.Hypoglycaemic HemiplegiaThis is a rare complication of acute hypoglycaemia in which the patient recovers fromthe hypoglycaemia with a transient hemiparesis lasting no more than 24 hours. Whenneuroimaging is performed it is rare to find an abnormality. There is no evidence of anysevere sequelae to this neurological manifestation of severe neuroglycopenia (Pocecco andRonfani, 1998).Fear of HypoglycaemiaBoth the children with diabetes and their parents worry about the prospect of a severe episodeof hypoglycaemia (Gold et al., 1997; Clarke et al., 1998; Gonder-Frederick et al., 1997;Marrero et al., 1997; Nordfelt and Ludvigson, 2005) (see Chapter 14). In one study severehypoglycaemia caused more fear than the prospect of an episode of diabetic ketoacidosis(Nordfelt and Ludvigson, 2005). Although there is little evidence that this modifies behaviourto attempt hypoglycaemia avoidance, such as relaxing glycaemic control or eating moresnacks, the adverse effects on quality of life should not be underestimated (Gold et al.,1997).Prediction of Nocturnal HypoglycaemiaOvernight glucose profiles have been shown to be extremely variable. As a result studies ofovernight hypoglycaemia have been unable to provide a ‘safe’ glucose value with which togo to bed. What is more useful is the fasting blood glucose concentration on the followingmorning. One study showed that the median fasting blood glucose at 07:00 hours wassignificantly lower following hypoglycaemia than a night with no hypoglycaemia (3.7[1.4–10.6] versus 8.5 [3.8–19.2] mmol/l, p = 0 00001) (Matyka et al., 1999a) (Figure 9.2).
206 HYPOGLYCAEMIA IN CHILDREN WITH DIABETES2015Glucose(mmol/l)1050hypoglycaemia no hypoglycaemiaFigure 9.2 Glucose values at 07.00 hours following a night of hypoglycaemia ( ) and a night of nohypoglycaemia ( ). Reproduced by permission of K. Matyka, PhD thesis ‘Nocturnal hypoglycaemiain prepubertal children with type 1 diabetes mellitus’, University of LondonThe occurrence of a ‘Somogyi phenomenon’, whereby overnight hypoglycaemia promotesglucose counterregulation and causes fasting hyperglycaemia, has not been demonstrated instudies of nocturnal hypoglycaemia in children (Porter et al., 1996; Beregszaszi et al., 1997;Matyka et al., 1999a).MANAGEMENT OF HYPOGLYCAEMIAThe management of acute hypoglycaemia will depend on the severity of the episode. TheInternational Society for Paediatric and Adolescent Diabetologists has provided guidelinesfor the management of acute episodes of hypoglycaemia based on severity (ISPAD, 2000).Blood glucose measurement is the only way to confirm hypoglycaemia if the diagnosisis uncertain and also confirm the return of the blood glucose to normal after treatment.Figure 9.3 shows the flow diagram for the management of hypoglycaemia.PreventionWhen faced in clinic with a child who is having recurrent episodes of hypoglycaemia, adetailed history should be obtained regarding the timing of hypoglycaemia, insulin regimen,dietary intake and the relation to periods of physical activity. This will enable an assessmentto be made of possible risk factors and inform how these may be avoided. If no obviouscause is found then other pathology should be sought, such as coincidental coeliac diseaseor the possibility of Addison’s disease, although these are relatively rare causes of recurrenthypoglycaemia (see Chapter 3).When contemplating preventive management the following aspects should be considered.
MANAGEMENT OF HYPOGLYCAEMIA 207Check blood glucose – Glucose meter test and formal laboratory glucose if possibleHypoglycaemiaMild SevereCONSCIOUS UNCONSCIOUSi.e. gag reflex intactOral glucosee.g. 5–15 grams of glucoseor 100 mls sweet drinkGlucogelOne ampoule orallyI.M. Glucagon<5 yrs 0.5 mg>5 yrs 1.0 mgSuccessIf no response in15 mins give 1–2mls/kg of 10%dextrose I.V.Repeat until thereis a clinicalresponse.As symptoms improve or normoglycaemia is restored add oral complex carbohydratee.g. biscuit, bread and so on.If unable to tolerate oral carbohydrate may need a glucose infusione.g. 5–10% glucose at maintenance rateNo successFigure 9.3 Management of hypoglycaemiaEducationGreat importance is placed on education in the management of type 1 diabetes and structurededucation programmes are now an essential part of any diabetes service provision. Despitethis, little validation has been made of the use of structured educational programmes inchildren. One study from Scandinavia has shown the benefits of a focused education package(Nordfelt et al., 2003). In this study families were given both written and video informationon diabetes. One group were given general information on diabetes management and theother was given material to educate about the importance and means of hypoglycaemiaavoidance. Although no differences in glycated haemoglobin were found between the two
208 HYPOGLYCAEMIA IN CHILDREN WITH DIABETESgroups, those who had the targeted intervention had a significantly reduced rate of severehypoglycaemia (Nordfelt et al., 2003).InsulinAs noted earlier, the DCCT suggested that attempts to intensify insulin regimens may increasethe risk of severe hypoglycaemia. Recent introductions of analogue insulins, however,indicate that improved glycaemic control does not always lead to hypoglycaemia, althoughfew studies have been designed specifically to examine the benefits of different insulinregimens on the risk of hypoglycaemia. One study that compared insulin lispro with soluble(short-acting) insulin as part of a basal bolus regimen, showed small but statistically signif-icant reductions in the prevalence of hypoglycaemia over a 30 day period when insulinlispro was being used (Holcombe et al., 2002). Other studies have found benefits of insulinanalogue regimens on nocturnal hypoglycaemia. One randomised cross-over study in adoles-cents compared insulin lispro and glargine, as part of a daily multiple injection regimen,to human soluble and isophane insulins. Nocturnal hypoglycaemia was 43% lower withthe analogue regimen, although no difference was observed in self-reported symptomatichypoglycaemia (Murphy et al., 2003). Another study in prepubertal children examined thebenefits of a thrice daily insulin regimen, where the evening dose of mixed insulin wasreplaced by a rapid-acting insulin analogue with the evening meal and isophane insulin beforebed (Ford-Adams et al., 2003). Although there was no difference in glycated haemoglobinbetween the two treatment arms, the prevalence of hypoglycaemia was lower in the earlypart of the night (22.00–04.00 hours) when the analogue was used.Although not every patient is suited to using insulin pump therapy, clinic-based studiesof CSII therapy have shown that more stable blood glucose control can be achieved withoutan increased risk of hypoglycaemia. In an American study describing the experience ofusing insulin pumps in a paediatric clinic, it was found that 50 adolescents on multipledaily injections experienced 134 episodes of severe hypoglycaemia per 100 patient-yearscompared to 76 episodes per 100 patient-years in the 25 adolescents who opted for pumptherapy (Boland et al., 1999).DietFew studies have examined the impact of dietary interventions on hypoglycaemia risk exceptfor nocturnal hypoglycaemia. The major dietary modification has been that of the introductionof a larger proportion of starch, as a form of long-acting carbohydrate, as part of the eveningsnack (Ververs et al., 1993; Kaufman et al., 1995; Detlofson et al., 1999; Matyka et al.,1999a). In these studies the benefits of starch have been inconsistent. One study found alower frequency of nocturnal hypoglycaemia, although capillary sampling was performedonly intermittently during the night and some episodes of hypoglycaemia may have beenundetected (Kaufman et al., 1995). Others found no beneficial effect of cornstarch on theprevention of nocturnal hypoglycaemia although blood glucose concentrations fell moreslowly, but in one study this occurred at the expense of promoting hyperglycaemia (Ververset al., 1993; Matyka et al., 1999a). Although not designed to examine the impact of diet onhypoglycaemia, a study of a low glycaemic index diet has been shown to improve glycaemic
CONCLUSIONS 209control without an increase in rate of hypoglycaemia, and appeared to have enhanced qualityof life (Gilbertson et al., 2001)ExerciseWhen adequate plasma insulin concentrations are available, exercise can lead to acutehypoglycaemia. However if exercise is performed at a time of relative insulin deficiency,hyperglycaemia with ketosis can occur. In addition, delayed hypoglycaemia may occur asmuscle glycogen stores recover mainly overnight (Admon et al., 2005; Tsalikian et al., 2005).Although few data are currently available regarding the most appropriate management ofplanned periods of physical activity, a number of guidelines have been proposed. The Inter-national Society for Paediatric and Adolescent Diabetologists has published guidelines onthe Internet (www.ispad.org). These recommend that careful monitoring of blood glucose isessential to match food and insulin to the intensity of exercise and that a reduction of insulinshould be considered. Additional slowly absorbed carbohydrate will be necessary, especiallyat bedtime, if exercise has been performed in the afternoon or early evening. From the dataavailable so far (Admon et al., 2005; Tsalikian et al., 2005), these guidelines do seem areasonable approach to the avoidance of both exercise related hypo- and hyperglycaemia.It is important, however, to work with the child and family to provide individually-tailoredrecommendations that are tried and tested for the child. The management of unpredictableepisodes of physical activity are likely to remain a problem until a cure for diabetesis found.CONCLUSIONS• Hypoglycaemia is a common problem for children with type 1 diabetes, especially youngchildren, and for their families.• Behavioural symptoms are more common in childhood than more typical autonomicsymptoms. The majority of episodes of nocturnal hypoglycaemia are totally asymptomatic.• Episodes of hypoglycaemia remain a significant barrier when striving for a degree ofglycaemic control that will delay or prevent the development of the microvascular compli-cations of diabetes.• Glucagon responses during hypoglycaemia are lost early in the course of type 1 diabetes.Epinephrine responses during overnight hypoglycaemia are blunted in both healthy chil-dren and those with type 1 diabetes and may contribute to the lack of symptoms of manyepisodes of hypoglycaemia overnight.• Concerns remain about the possible long-term implications of hypoglycaemia in terms ofcognitive dysfunction although hyperglycaemia may also be important.• More recent data suggest that novel insulin analogues and regimens may enable improve-ments in glycaemic control to be achieved without a concomitant increase in the risk ofhypoglycaemia.
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