Endocrine system


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Endocrine system

  1. 1. 9 Endocrine system Diabetes mellitus 582 • Management 604 • Physiological principles of glucose and • Monitoring 628 insulin metabolism 582 Thyroid disease 630 • Epidemiology and classification 587 • Physiological principles 630 • Aetiology and pathogenesis 589 • Hypothyroidism 633 • Natural history 591 • Hyperthyroidism 637 • Clinical features 593 • References and further reading 643 • Complications 593 Endocrine control of physiological functions represents broadly targeted, slow acting but funda- mental means of homeostatic control, as opposed to the rapidly reacting nervous system. In endocrine disease there is usually either an excess or a lack of a systemic hormonal mediator, but the cause may be at one of a number of stages in the endocrine pathway. Thyroid disease and diabetes mellitus represent contrasting extremes of endocrine disease and its management. Diabetes is one of the most serious and probably the most common of multisystem diseases. Optimal control of diabetes requires day-to-day monitoring, and small variations in medication dose or patient activity can destabilize the condition. Therapy requires regular review and possible modification. Furthermore, long-term complications of diabetes cause considerable morbidity and mortality. Thyroid disease is a disorder of thyroid hormone production that has, compared to diabetes, equally profound overall effects on metabolic and physiological function. However, it causes few acute problems and has far fewer chronic complications. Moreover, management is much easier, requiring less intensive monitoring and few dose changes. Furthermore, control is rarely disturbed by short-term variations in patient behaviour.
  2. 2. 582 Chapter 9 • Endocrine system Diabetes mellitus Diabetes mellitus is primarily a disorder of • Rapid: in certain tissues (e.g. muscle), insulin carbohydrate metabolism yet the metabolic facilitates the active transport of glucose and problems in properly treated diabetes are not amino acids across cell membranes, usually troublesome and are relatively easy to enhancing uptake from the blood. control. It is the long-term complications of • Intermediate: within all cells, insulin diabetes that are the main causes of morbidity promotes the action of enzymes that convert and mortality. People with diabetes suffer far glucose, fatty acids and amino acids into more from cardiovascular and renal disease more complex, more stable storage forms. than other people, and diabetes is the principal • Long-term: because of increased protein cause of acquired blindness in the West. Most synthesis, growth is promoted. people with diabetes do not die from metabolic One important consequence is the prompt crises such as ketoacidosis but from stroke, MI (though not complete) clearance of glucose from or chronic renal failure. the blood after meals. Glucose would otherwise Diabetes is associated with obesity and lack of be lost in the urine because of the kidney’s exercise, and the steady increase in prevalence limited capacity for reabsorbing glucose filtered in the West is being reproduced in large parts of at the glomerulus. the developing world as they adopt that life- style. Diabetes is in danger of becoming almost pandemic. Particularly worrying is the rise in the Glucose transport incidence of diabetes of both types in ever Glucose uptake into cells across the cell younger patients. This threatens to put an intol- membrane is dependent on the concentration erable strain on health services, particularly in gradient between the extracellular medium (e.g. developing countries. blood plasma, gastrointestinal contents) and the cell interior. However, because glucose is such an important metabolite, there exist a Physiological principles of glucose and number of membrane transport pumps or facili- insulin metabolism tators in certain tissues. There are special insulin- Insulin action DIET typical body cell Insulin is the body’s principal anabolic absorption hormone. It expands energy stores during times into plasma PROTEIN of adequate nutrition against times of food Plasma shortage. Opposing this action are several cata- AMINO AMINO ACID bolic ‘counter-regulatory’ or ‘stress’ hormones ACID that mobilize glucose for use when increased GLYCOGEN energy expenditure is necessary. The most Plasma important of these are adrenaline (epinephrine), GLUCOSE GLUCOSE corticosteroids, glucagon, growth hormone and growth factors. These two opposing systems Energy FAT work in harmony to maintain glucose home- ostasis. Insulin also enhances amino acid utiliza- Figure 9.1 Simplified scheme showing the anabolic tion and protein synthesis, the latter action actions of insulin. Insulin aids the uptake of metabolites into being shared with growth hormone. body cells and enhances the action of enzymes that utilize Insulin action has three main components them as precursors to synthesize more complex molecules. (Figure 9.1): Note: not all actions shown occur in all body cells.
  3. 3. Physiological principles of glucose and insulin metabolism 583 independent sodium-dependent transporters down is inhibited. Tissue growth and cell divi- (SGLT) for uptake from the GIT into intestinal sion are also promoted by enhanced nucleic acid cells and a variety of insulin-dependent and (DNA, RNA) synthesis, amino acid assimilation insulin-independent glucose transporters (GLUT) and protein synthesis. for most other tissues or organs (Table 9.1). In muscle and adipose tissue the transporter Overall effect depends on an insulin-requiring active pump for glucose uptake, so insulin deficiency deprives Only a general appreciation of how insulin and them of glucose. Other cells, particularly in the the catabolic hormones control everyday meta- liver, brain, kidney and GIT, do not absolutely bolic variations is given here (see also References require insulin for glucose uptake, but diffusion and further reading). is nevertheless facilitated by it. In the liver, enhanced phosphorylation of glucose drives Anabolic actions of insulin intracellular concentrations down, encouraging Following a meal, glucose is absorbed from the uptake. Insulin lack does not deprive tissues such GIT into the blood and rapidly transported into as these of glucose; on the contrary, the hyper- the cells, to be converted into forms suitable for glycaemia associated with diabetes can produce storage and later use. intracellular glucose overload, and this may be In the liver some glucose is converted into responsible for some diabetic complications (p. glycogen and stored but most is converted into 593). This is particularly relevant to tissues such lipid (free fatty acid, FFA [or non-esterified fatty as nerves, which are freely permeable to glucose. acid, NEFA], and triglyceride). Lipid is released Insulin also facilitates the uptake of amino into the blood as very-low-density lipoprotein acids into liver and muscle, and of potassium (VLDL), to be taken up and stored in adipose into most cells. This latter effect is exploited tissue. However, the release of glucose into the therapeutically for the rapid reduction of blood is inhibited. Hepatic regulation of glucose hyperkalaemia (see Chapter 14). output is an important mechanism for limit- ing the uptake of glucose into tissues where transport is independent of insulin. Metabolic effects In adipose tissue, fat breakdown is inhibited By facilitating certain enzymes and inhibiting and glucose uptake promoted. The glucose others, insulin has wide-ranging effects on inter- provides glycerol for esterification with FFAs, mediary metabolism in most tissues (Table 9.2; and the resulting fat is stored. Adipose tissue also Figure 9.1). The synthesis of the energy stores takes up the fat-containing chylomicrons (glycogen in liver and skeletal muscle, fat in liver obtained by digestion (see Chapter 3). In muscle, and adipose tissue) is facilitated, and their break- fat metabolism is inhibited and glycogen is Table 9.1 Insulin requirement and transporters for glucose uptake into different tissues Tissues not requiring insulin Transporter Tissues requiring insulin Transporter Gastrointestinal – uptake SGLT Adipose Gastrointestinal – release to blood GLUT2 Muscle – skeletal, cardiac, smooth GLUT4 Liver GLUT7 Other tissues Nerves, brain GLUT1,3 Kidney tubules GLUT2, SGLT Eye – retinal vessels, lens SGLT Leucocytes GLUT Blood vessel endothelium GLUT Pancreatic beta cells GLUT2 SGLT, sodium-dependent glucose transporter; GLUT, glucose transporter.
  4. 4. 584 Chapter 9 • Endocrine system Table 9.2 Metabolic effects of insulin Metabolite Process Tissue Liver Muscle Adipose Carbohydrate Increased • Glycogen synthesis (glycogenesis) ✓ ✓ ↔ • Glucose oxidation (glycolysis) ✓ ✓ ✓ Decreased • Glycogen breakdown (glycogenolysis) ✓ ✓ ↔ • Glucose synthesis (gluconeogenesis) ✓ ↔ ↔ Lipid Increased • Fat synthesis (lipogenesis) ✓ ↔ ✓ • Utilization of dietary fat ✓ ↔ ✓ Decreased • Fat breakdown (lipolysis) ↔ ↔ ✓ • Fatty acid oxidation (ketogenesis) ✓ ✓ ✓ Protein Increased • Protein synthesis ✓ ✓ ✓ Decreased • Protein breakdown (proteolysis) ✓ ✓ ↔ Nucleic acid Increased • DNA and RNA synthesis ↔ ✓ ↔ • Cell growth and division ↔ ✓ ↔ ✓, insulin has important effect (increase or decrease) on process in this tissue; ↔, no effect. synthesized, which increases glucose availability It will be explained below that obese type 2 for immediate energy needs. Amino acid uptake patients may not at first have an absolute defi- is promoted so that growth can be continued. ciency of insulin; rather, there is a degree of insulin resistance. This may be described as a Catabolic actions of counter-regulatory relative lack because the result is the same; more- hormones over, eventually their insulin levels do fall. There During stresses such as ‘fight or flight’, infection are important differences between the physio- or any major trauma, catabolic hormones reverse logical effects of partial (or relative) deficiency these processes. Blood glucose is rapidly raised to and total insulin deficiency. supply energy for the muscles and if this is insuf- ficient fats can also be mobilized. Peripheral Partial deficiency (type 2) oxidation of FFAs produces large amounts of energy, but in the liver excess acetyl-CoA is Even small amounts of insulin will prevent produced. This is condensed to produce high- severe metabolic disruption, especially acceler- energy ketoacids such as acetoacetate, which ated fat metabolism, i.e. ketosis. Thus, although many tissues can utilize in small amounts. In fasting blood glucose levels may be raised, the insulin insufficiency these ‘ketone bodies’ may main problems only arise after meals; these arise accumulate in the plasma, causing ketoacidosis. from impaired glucose transport and cellular uptake resulting in impaired clearance from the blood. Adipose and muscle tissue cannot take up Insulin deficiency glucose efficiently, causing it to remain in the blood, and glucose deficiency in muscle may The consequences of insulin deficiency, and thus cause weakness. Becuse other tissues cannot many of the clinical features of diabetes, can be compensate sufficiently to assimilate the deduced from these considerations (Figure 9.2). entire postprandial glucose load, the blood
  5. 5. Physiological principles of glucose and insulin metabolism 585 Subsequently fat is mobilized, mainly from DIET adipose tissue, so that plasma triglyceride and typical body cell FFA levels rise, as does lipoprotein. These supply absorption energy needs for a little longer while the into plasma negative PROTEIN nitrogen patient loses yet more weight. The brain cells Plasma balance switch to metabolizing the hepatically produced AMINO AMINO ACID keto-acids. Fat stores are not replenished, and ACID eventually may be exhausted. Finally, protein GLYCOGEN must be broken down into amino acids, which Plasma can be converted to glucose in the liver (gluco- GLUCOSE GLUCOSE FATS neogenesis), at the expense of lean muscle mass. Other than in uncontrolled diabetes, this process Energy Urinary normally occurs only in times of prolonged star- loss Ketones Lipoprotein vation; it is a desperate remedy that is akin to burning the house down to keep warm. Further, Figure 9.2 Metabolic consequences of insulin lack. without insulin, any glucose so produced cannot Cellular uptake of glucose is prevented so that after be utilized effectively anyway. This situation is exhausting their glycogen supplies, cells need to use fats inevitably fatal within months. and even protein for their energy needs. Compare with Thus many of the clinical problems in type Figure 9.1. Note: not all actions occur in all body cells. 2 diabetes are a direct consequence of hyperglycaemia, while in type 1 diabetes there is glucose level rises causing hyperglycaemia also disrupted intracellular metabolism. In ( 11 mmol/L). addition, chronic complications occur in both When the blood glucose level increases so that types, related to both hyperglycaemia and the concentration in the glomerular filtrate dyslipidaemia. These are discussed below. exceeds the renal threshold (see Chapter 14, p. 876), glucose is lost in the urine (glycosuria). Urinary glucose acts as an osmotic diuretic Insulin physiology carrying with it large volumes of water (polyuria and urinary frequency), resulting in excessive Insulin (molecular weight about 5800 Da) is thirst and fluid intake (polydipsia). Because of composed of 51 amino acids in two chains of reduced fat uptake by adipose tissue, plasma 21 (A chain) and 30 (B chain) amino acids lipid levels rise, especially triglycerides (dyslipi- connected by two disulphide bridges. It is syn- daemia). LDL is relatively unaffected but HDL is thesized in the pancreatic islet beta-cells. Other reduced, increasing atherogenic risk (Chapter 4). cells in the islets are the alpha-cells (producing Protein synthesis may be reduced but patients glucagon) and the delta-cells (producing somato- are often still relatively obese. However, they statin). Islet cells altogether comprise less than usually do lose weight in the weeks before first 3% of the pancreatic mass. Insulin is stored in diagnosis, in part due to dehydration. granules in combination with C-peptide as proinsulin (molecular weight 9000 Da), which is split before release into the portal vein. Insulin Total deficiency (type 1) has a plasma half-life of only about 5 min. With no insulin at all there is severe hypergly- Approximately 50% of insulin is extracted by the caemia at most times. This may raise the blood liver, which is its main site of action, and after osmotic pressure sufficiently to cause neurolog- utilization it is subsequently degraded. Eventu- ical complications including coma; this is ally, kidney peptidase also metabolizes some discussed on pp. 594–596. Cellular metabolism is insulin. C-peptide is less rapidly cleared and is profoundly disturbed. No glucose is available for thus a useful index of beta-cell function. The energy metabolism, and the first result is a main control of insulin level is plasma glucose: a depletion of liver and muscle glycogen stores. rise stimulates both the release and the synthesis
  6. 6. 586 Chapter 9 • Endocrine system of insulin. Amino acids and possibly fats also is a delayed second phase of secretion after promote insulin release (Figure 9.3). about 45 min. Appoximately 5–10 units are A wide variety of other neuronal, endocrine, secreted with each meal. pharmacological and local influences on insulin Thus the plasma insulin concentration curve release have been identified (Figure 9.3), but normally closely parallels the plasma glucose their physiological or pathological significance concentration curve throughout the day, reflect- is not established. Adrenergic beta-receptors ing every small change in nutrient supply or mediate release, so beta-blockers can theoreti- demand (Figure 9.4). Considering these subtle cally inhibit this, though stimulation of and sometimes rapid adaptations, it can be inhibitory adrenergic alpha-receptors, magnified appreciated how far current therapeutic methods during the hyperglycaemic stress response, fall short of mimicking the physiological ideal. usually predominates. In non-diabetics, the total daily secretion of Interestingly, glucose is a more powerful insulin is probably rather less than the average stimulant orally than parenterally, and various daily requirement in type 1 diabetes of 50 units gut hormones have been implicated in this. of exogenous insulin, mainly because of losses at Glucagon also promotes insulin release, possibly the injection site. to facilitate cellular uptake of the glucose that it causes to be released into the plasma. Amylin The 37-amino acid peptide amylin is co-secreted Pattern of secretion with insulin from beta-cells. It appears to It is important to note also that there is a contribute to glucose regulation by a local continuous basal level of insulin secretion (paracrine) action on islet cells, which moderates throughout the 24 h, independent of food intestinal glucose uptake, thereby reducing the intake, which contributes to the regulation of load presented to the pancreas, or by suppressing metabolism and promotes glucose uptake into glucagon secretion. In diabetes, amylin defi- cells. This amounts to about 1 unit/h. Following ciency parallels that of insulin and it is believed a meal there is an additional bolus secreted, that patients whose postprandial hypergly- which is biphasic. Within 1 min of blood caemia is not adequately controlled by conven- glucose levels rising, preformed insulin is tional therapy may benefit from amylin released from granules in beta-cells into the agonists, although none is yet in clinical use. blood. This release is stimulated by certain antidiabetic agents (insulin secretagogues) and Insulin receptors is the first component to be compromised in early diabetes. Should hyperglycaemia persist, These are present on the cell surfaces of all further insulin synthesis is stimulated and there insulin-sensitive tissues and are normally down- Glucose Amino acids (some) Somatostatin Hormones (e.g. glucagon, incretin, CCK) Parasympathetic nervous system/ BETA-ISLET Beta-blocking drugs cholinergic agents CELL Thiazides Sympathetic nervous system – beta-adrenergic agents Sympathetic nervous system – alpha-adrenergic agents Sulphonylureas/meglitinides INSULIN Corticosteroids/oral contraceptives Figure 9.3 Factors affecting the release or action of insulin. CCK, cholecystokinin. –––––● inhibition/antagonism; –––––● stimulation/potentiation. ●
  7. 7. Epidemiology and classification 587 Mid- Mid- morning afternoon Evening 10 Breakfast snack Lunch snack meal 80 Blood glucose (mmol/L) Plasma insulin (mU/L) Fasting blood glucose level 5 40 Basal plasma insulin level 10 0 0 2400 0600 1200 1800 2400 Time (hours) Figure 9.4 Schematic representation of normal diurnal variations in blood glucose and plasma insulin levels. As the blood glucose level rapidly rises after a meal, it is closely followed by an increase in insulin level to limit the rise. The insulin returns towards the basal level as blood glucose reaches the normal fasting level once more. Note how the two substances follow almost parallel curves, the insulin a little later than the glucose. The small but positive constant basal insulin level emphasizes that insulin has functions other than just dealing with dietary glucose. Note: this diagram does not differentiate the two phases of insulin release. regulated by insulin, especially if it is present at 2 diabetes insulin is secreted but is either continuously high levels, e.g. the hyperinsuli- inadequate or insufficiently effective to meet naemia of over-eating, obesity or obesity-related metabolic needs. type 2 diabetes. This may account for the The current WHO definition of diabetes is reduced insulin sensitivity (insulin resistance) based on standardized measurements of plasma found in some patients and the beneficial effect glucose concentrations. It defines three classes, of weight reduction, especially of abdominal fat, diabetes, impaired glucose tolerance and on glucose tolerance: there is a vicious cycle impaired fasting blood glucose (Table 9.3). whereby hyperglycaemia and reduced insulin Patients in the second category are borderline action reinforce one another. Long-term insulin and about half will progress to frank diabetes treatment also often gradually reduces the eventually (up to 5% per year). However, they insulin requirement, perhaps owing to reduced need not be treated immediately, depending on glucose levels. However, there is still much to be age and the presence of other risk factors: older learned about the interactions between insulin, patients or those with no cardiovascular risk insulin receptors and carbohydrate metabolism. factors may just be monitored. More recently the category of impaired fasting glucose has been introduced in an attempt to identify at an even earlier stage those with latent or ‘pre-diabetes’ Epidemiology and classification who should be monitored. It is a less reliable predictor but has the advantge that it does not The hallmark of diabetes is hyperglycaemia, require a glucose tolerance test (see below). owing to abnormalities of insulin secretion or Often, a single random plasma glucose of action. There are two primary forms of diabetes 11.1 mmol/L (blood glucose 10 mmol/L) is and a variety of minor secondary ones. In type 1 sufficient for diagnosis in a patient with classic diabetes there is usually gross destruction of the symptoms, although this should be confirmed insulin-secreting pancreatic beta-cells. In type with a fasting plasma glucose 7 mmol/L.
  8. 8. 588 Chapter 9 • Endocrine system Table 9.3 WHO definitions of diabetes mellitus (based on plasma glucose levels, as measured in laboratory) Class Plasma glucose (mmol/L) Fasting OGTT at 2 h Diabetes mellitus 7 and/or 11.1 Impaired glucose tolerance (IGT) 7 and 7.8–11.1 Impaired fasting glucose (IFG) 6.1–7 Normal fasting glucose 6.1 and 7.8 If whole blood is used (as obtained by finger prick) all figures would be approx. 10% lower (e.g. 6.1 and 10 mmol/L for diabetes mellitus). The apparently non-uniform thresholds derive from conversion from old mg/100 mL units, as still used in North America. OGTT, oral glucose tolerance test. Laboratories may report plasma glucose levels, as Classification specified by the American Diabetic Association diagnostic criteria, whereas finger prick tests Primary diabetes – type 1 and type 2 measure blood levels; nevertheless, it is customary always to refer to blood glucose in In the vast majority of cases there is direct discussing diabetes. In borderline cases the oral damage to the pancreatic islet cells. Different glucose tolerance test (OGTT) can be attempts to classify diabetes comprehensively performed: the patient’s blood glucose is have been confounded by the use of criteria that measured before and at 2 h after a standardized are not mutually exclusive (e.g. age at onset, 75-g glucose load, given orally following an patient build or need for insulin). For example, overnight fast. some older (‘maturity onset’ or type 2) patients eventually require insulin, some older patients need it from the start (‘latent autoimmune diabetes in the adult’, LADA) and a few younger Epidemiology patients may not (‘maturity onset diabetes of the young’, MODY). Whether the patient needs Diabetes is known to affect more than 2% of the insulin may be the most practical distinction, UK population, and probably as many again are but does not correspond consistently with other likely to have impaired glucose tolerance or even important parameters. frank diabetes if screened. The prevalence varies A classification based on the pathogenesis of considerably between populations. For example, the pancreatic damage is now accepted as the Europeans are prone to type 1, especially in most meaningful. This distinguishes two broad northern Europe, whereas the incidence in Japan types (Table 9.4), which correspond roughly with is less than 10% of that in Finland. insulin dependency. The key criterion is the mode Type 2 seems to be related partly to the afflu- of pancreatic damage, but many other distinc- ence of a population, possibly through the tions follow from this classification, including prevalence of obesity, inactivity or both, which natural history, family history and patient type. are major risk factors. However, genetic factors These will be discussed in the following sections. are also important. In some ethnic groups the prevalence is very high, e.g. in some Pacific Secondary diabetes Islanders and the North American Pima Indians it reaches 50%. Among South Asian immigrants A minority of cases with identifiable primary to the UK it is five times that in the host popu- causes (e.g. severe pancreatitis, steroid-induced lation, suggesting a possible genetic suscepti- diabetes) do not fit readily into either of the bility to changed environmental factors, e.g. a conventional categories. They may or may not diet richer in fats and sugar. require insulin for treatment (p. 591).
  9. 9. Aetiology and pathogenesis 589 Table 9.4 Comparison of the main types of primary diabetes mellitus Type 1 Type 2 Endogenous insulin Absent Present Insulin deficiency Absolute Relative or partial Insulin receptor defect? Insulin resistance Usually absent May be present Pancreatic islet damage Severe (destruction) Slight/moderate Immunology Auto-immune; islet cell antibodies No antibodies demonstrated Usual age of onset 30 years 40 years Build of patient Thin Obese (usually) Therapeutic class Insulin-dependent (IDDM) Non-insulin-dependent (NIDDM; but may require insulin) Genetics Weak family history; HLA-linked Strong family history Ketoacidosis prone? Yes No Aetiology and pathogenesis patients. However, interestingly, it is not these anti-islet antibodies that mediate cell destruction but T-cells; the islets are invaded by inflamma- Primary diabetes tory cells causing insulitis. Insulin autoanti- bodies may also be found but their significance Despite having similar clinical pictures and is uncertain. As is usual with autoimmune complications, types 1 and 2 primary diabetes disease, there is rarely a strong family history: have very different causes (Table 9.5). siblings or children of people with type 1 diabetes have about a 5% chance of developing the disease. However, there is a correlation with Type 1 diabetes the patient’s HLA tissue type (see Chapter 2) In type 1 diabetes the islet beta-cells are almost and in a minority of patients an association with completely destroyed by an autoimmune other autoimmune diseases, especially of process. Antibodies against all islet cells, and endocrine tissues (e.g. thyroiditis, pernicious beta-cells specifically, are found in 80% of anaemia). Table 9.5 Aetiology and pathology of primary diabetes Type 1 Type 2 Risk factors HLA antigens (DR3, DR4) Family history Over-eating; lack of exercise Toxin? Amyloid? Ethnic group Trigger factors Viral infection Obesity Metabolic stress/excessive demand Metabolic stress/excessive demand Environmental toxin? Pathogenesis Rapid autoimummune destruction of islet cells Gradual islet cell degeneration / depletion Peripheral insulin receptor defect?
  10. 10. 590 Chapter 9 • Endocrine system Overt diabetes may follow many years of • Absolute insulin deficiency, i.e. reduced subclinical pancreatic damage, and when it insulin secretion. occurs there is usually less than 10% of func- • Relative insulin deficiency: not enough tional islet cell mass remaining. Clinical onset is insulin is secreted for metabolic increased usually abrupt, over a few weeks, and often asso- needs (e.g. in obesity). ciated with, or precipitated by, a metabolic stress • Insulin resistance and hyperinsulinaemia: a such as an infection, which acutely increases peripheral insulin utilization defect. insulin demand beyond capacity. This might In most cases type 2 diabetes is associated with account for the winter seasonal peak in inci- obesity (particularly abdominal obesity) on dence and also the brief temporary remission first presentation, and in a quarter of all people that frequently follows, as the infection remits with diabetes simple weight reduction reverses and the marginal insulin levels once again just the hyperglycaemia. This is commonly associ- compensate. Subsequently, full-blown disease ated with peripheral insulin resistance owing irreversibly takes hold. As with other autoim- to receptor-binding or post-receptor defects. mune diseases, viral infection may be causing Obesity and reduced exercise also contribute the expression of a normally suppressed HLA to insulin resistance and are modifiable risk receptor, which subsequently activates lympho- factors for type 2 diabetes. The resultant hyper- cytes (see Chapter 2). Other environmental trig- glycaemia induces insulin hypersecretion, gers such as toxins or certain foods (including hyperinsulinaemia and insulin receptor down- milk protein) may also be involved. regulation, i.e. further insulin resistance. Hyper- Autoantibodies may be found in some glycaemia itself is known to damage beta-cells patients up to 15 years before the onset of acute owing to the direct toxic effect of excessive intra- disease. This could eventually provide a means cellular glucose metabolism, which produces an of early identification of prediabetes, so that excess of oxidative by-products; these cannot be they may be treated prophylactically, possibly destroyed by natural scavengers such as catalase by immunotherapy. However, such markers are and superoxide dismutase. The vicious cycle also often found in close relatives who never eventually depletes (‘exhausts’) the beta-cells, develop the disease, and the chance of the intrinsic insulin levels fall and some patients identical twin of a diabetic patient subsequently may eventually come to require exogenous developing diabetes is less than 50%. The insulin therapy. Thus, type 2 diabetes is usually a introduction of the category of ‘impaired progressive disease, although the late onset fasting glucose’ was another attempt at early usually means that some patients die before identification of potential sufferers. requiring insulin. Thus it seems that in type 1 diabetes there is a There is still debate as to the primary defect of genetically determined HLA-dependent suscepti- type 2 diabetes. It has also been proposed that bility that requires an environmental trigger for the amyloid deposits (insoluble protein) long full expression. Following contact with this known to be found in the pancreas of type 2 trigger, which may never be encountered, swift patients are related to abnormalities in amylin deterioration and complete insulin dependence secretion (p. 586) and contribute to the are inevitable. There is still considerable ignor- pancreatic defect. ance of the relative contributions of genes and There is an association between abdominal environment and of specific environmental obesity, hyperinsulinaemia, insulin resistance, factors. hyperlipidaemia, type 2 diabetes and hyperten- sion, and this combination of risk factors is Type 2 diabetes termed metabolic syndrome. However, despite These patients have one or more of the following much research, as yet it is not known which of fundamental abnormalities, and in established these factors (if any) is the prime cause, or if disease all three commonly coexist: there is another underlying reason.
  11. 11. Natural histor y 591 Genetics Natural history The genetic component in type 2 diabetes is much greater than in type 1. A family history is Onset very common, often involving several relatives. Identical twins almost always both develop the About 80–90% of diabetic patients have type 2 disease, and offspring with both parents having diabetes, which tends to occur late in life, hence diabetes have a 50% chance of developing the the obsolete description ‘maturity onset’. Onset disease. The ‘thrifty gene’ hypothesis proposes is usually insidious and gradual, patients toler- that the ability to store fat efficiently – and ating mild polyuric symptoms perhaps for many hence develop obesity – conferred a survival years. advantage in more primitive societies where The other 10–20% have type 1 diabetes and famine was a regular phenomenon, hence its require insulin at the outset. Almost invariably persistence in the genome. This may explain they become ill at an early age: the peak onset why some pre-industrial groups (e.g. Pacific of type 1 is around puberty, starting most Islanders) readily develop diabetes when commonly in the winter months. Although the exposed to the industrialized lifestyle. disease may be present subclinically for some considerable time (months, or possibly years), clinical onset is invariably abrupt. Secondary diabetes Most diabetes results from primary defects of Presentation the pancreatic islet cells. However, there are occasionally other causes of ineffective Type 2 diabetes is usually first diagnosed insulin action, impaired glucose tolerance and following one of three common presentations hyperglycaemia (Table 9.6). (Table 9.7): Table 9.6 Some causes of secondary diabetes General mechanism Aetiology Example Hepatic glucose metabolism defect Liver failure Viral hepatitis, drugs Pancreatic destruction Cirrhosis Alcoholism Pancreatitis Anti-insulin hormones Corticosteroids Cushing’s disease Steroid therapy Pregnancy (‘gestational diabetes’) Major trauma/stress Growth hormone Acromegaly Adrenaline (epinephrine), etc. Phaeochromocytoma Glucagon Glucagonoma Thyroid hormones Hyperthyroidism Major trauma/stress Adrenergic drugs Hyperglycaemic/anti-insulin drugs Thiazide diuretics, diazoxide Oral contraceptives Insulin antibodies Autoimmune disease Abnormal insulin receptors Congenital lipodystrophy
  12. 12. 592 Chapter 9 • Endocrine system • About half of patients first complain of some time and then have undergone some major increasing polyuria and/or polydipsia. stress such as MI or serious infection. Another • In about a third it is a chance finding of glyco- possible trigger factor could be starting a drug suria or hyperglycaemia at a routine medical that impairs glucose tolerance, e.g. a thiazide examination. diuretic or an atypical antipsychotic. Such • In less than 20% of cases the patient stresses may also uncover latent disease in a less complains of symptoms subsequently found dramatic manner. to result from a complication secondary to Unfortunately, a severe acute presentation is diabetes. far more common at the onset of type 1 disease. This is usually associated with some metabolic Type 2 patients may be asymptomatic or may stress (e.g. infection), and presents with rapid have been only mildly symptomatic for several weight loss, weakness, extreme thirst, severe years. Commonly, they ignore these symptoms polyuria, urinary frequency and multiple or attribute them to ageing, and only present nocturia. Some may even go on to acute meta- when classical symptoms such as polyuria, thirst, bolic decompensation (ketoacidosis) and even tiredness or recent weight loss (even though the coma, being practically moribund on hospital patient may still be relatively obese) become admission. Following recovery with insulin unacceptable. In many other cases their diabetes therapy there may follow some months of is only detected when they undergo a medical apparent remission with a reduced or absent examination, e.g. for insurance purposes or a insulin requirement, the so-called ‘honeymoon new job. Alternatively, the complaint may be of period’, but these patients then deteriorate an infective complication not obviously linked rapidly. Before the isolation and therapeutic use to diabetes, at least not in the patient’s mind, of insulin in the 1920s they inevitably died such as recurrent candida infections or boils, a shortly thereafter. non-healing foot lesion or a persistent urinary- tract infection. Rarely, as the complications proceed insidiously even during this early period, the primary reason for consultation may Progression result from vascular disease, nephropathy, neuropathy, retinopathy or impotence. In some Insulin secretion in type 2 diabetes declines cases IHD, even MI, is the first presentation. relatively slowly, but up to one-third of patients A common manifestation of the complications may eventually need exogenous insulin, i.e. they is the ‘diabetic foot’. The patient presents with are ‘insulin-requiring’ as opposed to insulin- a possibly gangrenous foot lesion, probably dependent. following a recent injury and subsequent In most type 1 diabetes, pancreatic beta-cell infection. destruction is already almost complete at diag- Only very rarely will a type 2 patient first nosis, and routine insulin requirements do not present with metabolically decompensated generally increase. However, in both types the disease (ketoacidosis). These patients will prob- multisystem complications progress throughout ably have had impaired glucose tolerance for life at rates that vary considerably between patients and will very likely be the eventual Table 9.7 Different presentations of type 2 diabetes cause of death. People with diabetes have a reduced life expectancy, although the prognosis Typical diabetic symptoms (see text) 55%(a) has greatly improved with advances in treat- Chance finding 30% ment. Younger patients have mortality rates of Complication – infective 15% up to five times that of the general population, – other 2% while for older ones it is about twice normal. The precise prognosis for any given patient will (a) Approximate figures; after Watkins (2003) (See References and depend on many factors, but particularly the further reading). overall consistency of control of blood glucose.
  13. 13. Complications 593 Clinical features Diabetic urine dries to leave a white glucose deposit, a clue that sometimes leads to diagnosis: there may be underwear stains or white specks Symptoms on the shoes of elderly males (from careless micturition). Severe plasma hyperosmolarity The symptoms of diabetes as summarized in may reduce the intraocular pressure, causing Table 9.8 are best understood in relation to their eyeball and lens deformity, and glucose pathogenesis. may alter lens refraction: both lead to blurred vision. This is sometimes a prodromal sign of hyperglycaemic crisis in type 1 diabetes. Symptoms due to hyperglycaemia The classic symptoms, which give diabetes Impaired metabolism and complications mellitus its name (‘sweet fountain’), are easily explained by the osmotic effect of the elevated The metabolic consequences of insulin lack were blood glucose levels that occur when glucose is discussed in detail above. The pathophysiology denied entry to cells. They are more pronounced of hyperglycaemia and ketoacidosis is now when the blood glucose level rises rapidly, e.g. considered. in decompensation or acute onset. The osmotic effect of chronic hyperglycaemia will to some extent be compensated by compensatory Complications hyponatraemia and an increased intracellular osmolarity (see Chapter 14). When the blood glucose level exceeds the Most complications of diabetes are due to either renal threshold (about 10 mmol/L), glucose acute metabolic disturbances or chronic tissue appears in the urine in large quantities. The damage. traditional method of distinguishing diabetes mellitus from diabetes insipidus – almost the only two idiopathic causes of chronic polyuria – Acute complications was simply to taste the urine: in the former case it is sweet, and in the latter literally insipid The most common acute complications are (tasteless). Glycosuria predisposes to urinary- disturbances in glycaemic control. Optimal tract infection, partly because of the favourable management of diabetes aims for a delicate growth medium presented to perineal organisms balance, preventing excessive glucose levels but and partly because diabetic patients are generally not forcing glucose levels too low. A variety of more susceptible to infection (see below). circumstances can drive the glucose level outside Table 9.8 Clinical features of diabetes Direct consequences of high blood glucose levels Polyuria, frequency, nocturia, polydipsia (osmotic diuresis) Visual disturbance (osmotic changes to intra-ocular pressure) Urethritis, pruritis vulvae, balanitis (urogenital infection) Metabolic consequences of impaired glucose utilization Lethargy, weakness, weight loss (intracellular glucose deficit) Ketoacidosis (increased fat metabolism) Long-term complications of hyperglycaemia and hyperlipidaemia Vascular disease, heart disease, renal disease, neuropathy, eye disease, infections, arthropathy
  14. 14. 594 Chapter 9 • Endocrine system these narrow limits, and if treatment is not glucose level of approximately 15–20 mmol/L, adjusted accordingly, the result is either excess or both hyperosmolar and metabolic problems insufficient glucose in the blood (Table 9.9). develop (Figure 9.5; Table 9.10). Blood glucose levels can exceed 50 mmol/L and this high osmotic load (which is also in the Hyperglycaemia/ketoacidosis extracellular fluid) cannot be matched within Causes, pathogenesis and symptoms those cells from which glucose is excluded owing Hyperglycaemia in treated diabetes usually to the absence of insulin. Thus, water is drawn arises because normal medication is somehow from the intracellular compartment and this omitted or becomes insufficient to meet an causes tissue dehydration. This particularly increased insulin requirement. Drugs that raise affects the brain where the resultant reduced blood glucose levels can also interfere with intracranial pressure leads to CNS depression. control. When diabetic control is lost, blood The skin is also dehydrated, and loses its elas- glucose rises and the symptoms develop gradu- ticity; this reduced skin turgor can be detected by ally over a number of hours. Above a blood pinching a fold of skin and noting its delay in Table 9.9 Causes of acute disturbances in diabetic control Hypoglycaemia Hyperglycaemia/ketoacidosis Excess (mis-measured?) dose Missed antidiabetic dose Potentiation of oral hypoglycaemic (drug interaction) Hyperglycaemic drugs, e.g. thiazides, steroids Missed meal; dieting Excess dietary intake Unexpected physical activity Metabolic stress, e.g. infection, surgery, pregnancy Excessively tight blood glucose control Alcohol INSULIN DEFICIENCY REDUCED increased glucose INTRACELLULAR HYPERGLYCAEMIA in glomerular GLUCOSE filtrate increased plasma osmolarity osmotic diuresis switch to fat metabolism polyuria, tissue dehydration hypovolaemia glycosuria ketoacidosis thirst hyperkalaemia Na/K depletion polydipsia CNS depression tachycardia hyperventilation confusion, coma hypotension Figure 9.5 Pathogenesis and clinical features of acute hyperglycaemia and ketoacidosis.
  15. 15. Complications 595 fatty acids, and the liver converts some of these Table 9.10 Clinical features of hyperglycaemia and to acid ketones that can be readily utilized as an ketoacidosis alternative energy source by many tissues. The resulting metabolic acidosis (diabetic ketoaci- Glycosuria, ketonuria dosis) is misinterpreted by the respiratory centre Polyuria, nocturia as carbon dioxide retention, resulting in an Thirst, polydipsia increased respiratory drive and hyperventilation. Hypotension Acidosis impairs oxygen dissociation from Hb, Rapid (bounding) pulse and respiration exacerbating the gasping (overbreathing, ‘air hunger’), and also causes peripheral vasodilata- Dry mouth, reduced skin turgor Visual disturbance tion, exacerbating the hypotension. Both respi- ratory rate and blood oxygen level fall as coma Hyperkalaemia, acidosis, ketonaemia supervenes. Ketoacidosis is more likely to Sweet smell of ketones on breath develop in type 1 patients, although fortunately Weakness, drowsiness, eventually coma it is uncommon. People with type 2 diabetes usually secrete sufficient insulin to prevent them developing springing back, but this is less conclusive in the ketoacidosis (except during severe stress), but elderly, in whom skin elasticity is already they may still suffer hyperosmolar non-ketotic reduced. hyperglycaemic states. This may result in coma In the kidney the high load of glucose in the and is associated with a higher mortality than glomerular filtrate, not all of which can be reab- ketoacidosis. sorbed, produces an osmotic diuresis. This results in a reduction in circulating fluid volume, leading to hypotension and reflex tachycardia. Management The high urine volumes also cause a loss of elec- Diabetic ketoacidosis is a medical emergency trolytes, especially sodium and potassium. with about a 15% mortality rate. Close moni- However, the plasma potassium level may be toring and very careful attention to the patient’s paradoxically high because acidosis inhibits the fluid and electrolyte balance and blood Na/K pump throughout the body, preventing biochemistry are essential (Table 9.11). Imme- intracellular potassium uptake (see below and diate attention is life-saving, but the patient may Chapter 14, p. 891). Osmoreceptors and baro- take several days to stabilize. receptors detect the electrolyte and fluid losses, IV soluble insulin is essential. An initial causing thirst, but as CNS depression and confu- bolus of about 6 units is followed by contin- sion develop the patient often cannot respond uous infusion (6 units/h). Fluid replacement by drinking. needs are estimated from measurements of the In the absence of glucose, many cells start to CVP and plasma sodium level. Hyponatraemia metabolize fat instead. Adipose tissue releases (‘appropriate hyponatraemia’, glucose having Table 9.11 Principles of the management of ketoacidosis Problem Treatment Underlying cause Discover and treat Hyperglycaemia and hyperosmolarity Insulin (soluble): small bolus plus continuous infusion Dehydration IV infusion: saline/dextran/plasma Acidosis Bicarbonate? Hyperkalaemia/potassium deficiency Careful potassium repletion, after correction of acidosis Hypoxaemia Oxygen, up to 60% initially
  16. 16. 596 Chapter 9 • Endocrine system osmotically displaced sodium in the plasma) Pathogenesis and symptoms and/or sodium depletion require 0.9% saline Hypoglycaemic symptoms fall into two main administration. However, if the dehydration has groups (Table 9.12). At glucose levels below caused hypernatraemia, especially in the non- about 4 mmol/L insulin release is inhibited ketotic patient, hypotonic saline (e.g. 0.45%) and the counter-regulatory hormones such as may be indicated. Severe hypotension or shock glucagon and adrenaline are released in an effort require plasma replacement (see Chapter 14 to raise blood glucose. At a glucose level below p. 903). Potassium replacement is difficult to 3.5 mmol/L the body responds by activating manage because the initial hyperkalaemia the sympathetic nervous system and adrenal masks a total body potassium deficit. However, medulla (the ‘fight or flight’ response). The once insulin is started and potassium moves consequent sympathetic/adrenal symptoms intracellularly, closely monitored IV potassium (Table 9.12) should provide the patient with a replacement is required. Acidosis will often preliminary warning (but see below). resolve spontaneously with conservative therapy As the glucose level falls below about as ketone production falls and existing ketones 2.5 mmol/L, neurological signs develop owing to are metabolized. Many clinicians would not use the deficiency of glucose in the brain. These bicarbonate unless blood pH was below 7.00 for neuroglycopenic features may be noticed more fear of overcompensating. by others than by patients themselves, although many patients do report an awareness of subjec- tive prodromes. Sometimes the signs are subtle Hypoglycaemia changes in mood or visual disturbances, but eventually there is almost always erratic behav- Causes iour resembling drunkenness. This has some- In all forms of diabetes, hypoglycaemia (blood times led to police arrest and delayed treatment, glucose 3 mmol/L) is much more common occasionally with fatal results. Frequent hypo- than symptomatic hyperglycaemia, and it glycaemic attacks may have a cumulative delete- develops very rapidly, sometimes within rious effect on higher brain function (cognition), minutes. Usually, either an excessive insulin especially in the elderly. All people with diabetes dose is accidentally injected (many patients have should carry, in addition to a readily available eyesight problems) or else the normal dose of sugar source such as dextrose tablets, a card or insulin or antidiabetic agent is not matched by an adequate dietary intake (Table 9.9). Insulin- induced hypoglycaemia is usually associated Table 9.12 Clinical features of hypoglycaemia with injections of short-acting insulin. Deliberate overdosing is not unknown. Adrenergic (autonomic) – enhanced sympathetic Hypoglycaemia induced by sulphonylurea activity antidiabetic drugs is rarer but more prolonged, • tremor, sweating more severe and more difficult to treat than • shivering, palpitations insulin-induced hypoglycaemia. The elderly are • anxiety, pallor especially prone, partly because the drugs are Neuroglycopenic – reduced CNS glucose delivery cleared more slowly and partly because of • drowsiness, disorientation, confusion impaired homeostasis. Drug interactions that • apparent drunkenness; aggression, might potentiate oral antidiabetic drugs are inappropriate behaviour considered on p. 615. Alcohol not only causes • convulsions, coma, brain damage; death hypoglycaemia by inhibiting hepatic gluconeo- Other effects – multiple or indirect pathogenesis genesis but also impairs the patients’ perception • hunger, salivation, weakness, blurred vision of it, reducing their ability to respond.
  17. 17. Complications 597 bracelet stating that they have diabetes and response is usually satisfyingly prompt, occur- should be given sugar if found acting strangely. ring within minutes. Glucagon injection can A patient’s ability to recognize ‘hypos’ (their usually be managed easily by patients’ relatives, hypoglycaemic awareness) should be checked who should be fully informed on how to regularly because it tends to diminish. Long- recognize and deal with hypoglycaemic term diabetes patients become less sensitive to episodes. Unless patients or their relatives are the warning signs and thus more vulnerable. taught to recognize the early signs, the patient This may result partly from autonomic may become comatose before being able to neuropathy and partly from reduced counter- correct it. regulatory hormone response. It is also possible Persistent hypoglycaemic attacks require that frequent attacks may reduce the patient’s reassessment of therapy. Dietary modification ability to recognize them. Awareness is pro- may be required (e.g. increased carbohydrate), gressively reduced by frequent hypogly- although this might compromise weight reduc- caemic episodes but may be at least partially tion efforts. Modern intensive insulin therapy restored by minimizing or eliminating episodes regimens aimed at producing ‘tight’ glycaemic through relaxing control slightly, more careful control have increased the likelihood of monitoring and patient education. hypoglycaemia, and a judgement of risk and Most of the adrenergic symptoms are medi- benefit has to be made when such regimens are ated by beta-receptors, and so may be antago- considered (p. 626). nized by concurrent beta-blocker therapy. Although this rarely presents a serious problem, such drugs should be avoided in people with Unstable diabetes diabetes if they already experience hypogly- A small proportion of people with type 1 caemic unawareness. Otherwise, there is no diabetes prove exceptionally difficult to control, contra-indication but a cardioselective beta- experiencing frequent episodes of hypogly- blocker is preferred. Theoretically, beta-blockers caemia, hyperglycaemia or both. They are vari- might help by preventing beta-mediated insulin ously termed brittle, unstable or labile. It is release (Figure 9.3), but this is swamped by the unlikely that this condition is inherent to their symptom-masking effect. disease, and specific causes are always sought. Poor compliance through error, ignorance or Management disability, e.g. visual problems measuring insulin Although both hypoglycaemia and hypergly- doses, unrecognized intercurrent illness and caemia can result in coma, there is rarely any drug interaction must first be eliminated. In problem distinguishing them, especially as rapid older patients with recurrent hypoglycaemia the blood glucose test stick methods are readily possibility of reduced hypoglycaemic awareness available. A test dose of glucose would clinch must be investigated. matters because hypoglycaemia will be very Recurrent hyperglycaemia/ketoacidosis is rapidly reversed, whereas glucose would have no more common in young patients and may significant effect, either helpful or harmful, in sometimes be associated with psychological or hyperglycaemia. In contrast, insulin given psychopathological factors such as teenage rebel- blindly would severely exacerbate hypogly- lion or illness denial, self-destructive impulses caemia and should never be given where there is or other emotional instability. A particular doubt. subgroup has been identified of slightly obese The conscious patient must take glucose females aged 15–25 years who may be covertly tablets, or sugar, chocolate, sweet tea, etc. Semi- manipulating their therapy adversely. Supervised conscious or comatose patients require IV IV therapy in some of these patients seems to glucose 20% or IM glucagon (1 mg). The resolve the problem temporarily.
  18. 18. 598 Chapter 9 • Endocrine system Chronic complications gies, supports the hyperglycaemia hypothesis. The extensive Diabetes Control and Complica- In many patients, even before diagnosis, wide- tions Trial (DCCT; 1992) confirmed that better spread damage occurs in the kidney, nerves, eyes control is associated with less severe complica- or vascular tree (Figure 9.6). These long-term tions in type 1 diabetes. The UK Prospective complications are to different degrees common Diabetes Study (UKPDS; 1998) supported the to both types of diabetes, and their prevention or same hypothesis in type 2 patients. treatment are the real challenges for diabetes Other hypotheses have been proposed. It management and research. could be that an as yet unidentified primary lesion in diabetes is responsible independently for both the hyperglycaemia and the complica- Pathogenesis tions. If so, correcting one would not neces- It is important to determine whether or not sarily improve the other. Some complications these chronic problems are a direct consequence could be secondary to the abnormal pattern or of hyperglycaemia. If so, then optimal control to amount of insulin secretion, which is not achieve normoglycaemia would be expected to completely rectified by conventional treatment. minimize them. Evidence has accumulated that For example, the hyperinsulinaemia seen in this is broadly true for the so-called microvas- many type 2 patients may contribute to blood cular complications (mainly kidney, eye, nerves). vessel disease (macrovascular complications) or The fact that similar complications arise in most hypertension. Alternatively, the abnormally types of diabetes, despite their different aetiolo- high levels of counter-regulatory hormones Hypertension NEPHROPATHY RETINOPATHY PROTEIN Small blood vessels GLYCATION Dermopathy MICROANGIOPATHY Arthropathy HYPERGLYCAEMIA NEUROPATHY POLYOL ACCUMULATION Cataract Stroke Ischaemic heart disease large blood vessels Peripheral vascular MACROANGIOPATHY disease (Atherosclerosis) Dyslipidaemia Platelet/clotting defect Infections Figure 9.6 Possible pathogenetic mechanisms of chronic diabetic complications. The central box lists the clinical features. Also shown is possible interlinking of pathogenetic mechanisms.
  19. 19. Complications 599 usually found in diabetes may be deleterious. result from a combination of this and direct The involvement of growth hormone and glycation of the sheaths of small nerve axons, insulin-like growth factor in angiopathy has e.g. sensory nerves. Similarly, glycation of the also been investigated but no clear pattern glomerular basement membrane probably causes detected. Finally, there seems to be a genetic the characteristic glomerular sclerosis of diabetic variation in the susceptibility to different nephropathy, although renal arterial disease complications, regardless of the degree of probably also contributes. Glycation of tendon glycaemic control. sheaths and joint capsules may be responsible Thus there is unlikely to be a simple answer, for the joint problems, particularly the stiffness but the general strategy of normalizing blood in hands and feet, that some patients suffer; glucose is well established as the best we glycation of collagen in skin sometimes gives it a currently have for minimizing complications. thickened, waxy appearance. The myocardium Three general mechanisms are proposed for the may also be affected, as may immune cells such pathological basis of the complications: protein as macrophages and leucocytes. glycation (glycosylation), abnormal polyol metabolism and accelerated atheromatous Polyol metabolism arterial changes. Some tissues do not require insulin for glucose transport into their cells (Table 9.1), relying Glycation instead simply on diffusion down a concentra- Normally, almost all body protein is to some tion gradient. Thus, while other tissues are extent glycated, i.e. glucose molecules from body glucose-depleted in diabetes, these will accumu- fluids are covalently bound to free amine groups late excess glucose in the presence of hypergly- on protein side chains. The degree of glycation is caemia. Being surplus to energy needs, some of directly proportional to the average blood the excess glucose is reduced to polyols such as glucose level. An accessible marker for this is sorbitol by the enzyme aldose reductase via an Hb glycation, particularly the HbA1c fraction. otherwise little used pathway (Figure 9.7). Other proteins, and also lipids and nucleopro- The resulting polyols are not readily elimi- tein, throughout the body are similarly affected. nated from the cells, possibly because they are In excess, one result is the formation of more polar than glucose and of greater molec- abnormal crosslinks between different regions of ular weight. Furthermore, low dehydrogenase protein chains. Protein configuration is thus activity, particularly in the eye lens and nerve changed, disrupting secondary and tertiary sheaths, means that they are not metabolized structure and hence function. Basement efficiently. The resultant accumulation of membrane proteins seem particularly susceptible osmotically active molecules draws water into to glycation, the result being thickening and the cells, causing them to expand, severely increased permeability (i.e. reduced selective disrupting their function and possibly killing barrier function). As basement membranes are them. Retinal blood vessels, the eye lens and present in most tissues, and especially in blood the glomeruli may be damaged in this way, vessels, this could account for the widespread, contributing to retinopathy, cataract and multisystem distribution of diabetic complica- nephropathy, respectively. It has long been tions. Chronic hyperglycaemia also results in known that an analogous intracellular accumu- oxidative stress through increases in mito- lation of galactitol in the lens is linked to the chondrial superoxide formation, producing high prevalence of cataracts in the inherited advanced glycation end-products (AGPs) that metabolic disorder galactosaemia. can cause a variety of damaging effects. A further abnormality may also contribute. Basement membrane damage in capillaries Myoinositol, an important intermediate in and smaller arterioles can cause microan- energy handling, may (although also a polyol) giopathy and subsequent ischaemia in almost instead of accumulating become deficient. By a any organ. Retinopathy is undoubtedly caused poorly understood series of steps this deficiency in part by this mechanism. Neuropathy may may impair nerve conduction (Figure 9.7).
  20. 20. 600 Chapter 9 • Endocrine system Normal pathway hexokinase GLUCOSE Glucose-6-phosphate GLYCOLYSIS hyperglycaemia excess glucose aldose reductase OSMOTIC SORBITOL DAMAGE ? and other polyols ? reduced MYOINOSITOL MYOINOSITOL IMPAIRED NERVE reduced Na pump activity uptake depletion CONDUCTION Figure 9.7 Polyol pathway and effects of polyol accumulation. Macroangiopathy Diabetes and hypertension. There is an Almost all people with diabetes suffer from association between diabetes (especially type 2) increased obstructive vascular disease owing to a and hypertension, as part of the metabolic greatly increased predisposition to atheroscle- syndrome. The precise cause and effect rosis. Several factors contribute to this. Because of relationships have not yet been elucidated. their more active lipid metabolism, people with Many hypertensives have insulin resistance, diabetes have raised plasma levels of triglycerides hyperinsulinaemia and impaired glucose toler- and lowered HDL, producing an unfavourable, ance, and insulin may have several hypertensive atherogenic lipoprotein ratio (see Chapter 4, actions including promoting renal sodium reten- Figure 4.28). Furthermore, many type 2 patients tion, increasing sympathetic vasconstrictor are initially hyperinsulinaemic and insulin may activity and directly increasing vascular reac- itself be a growth factor for atheroma. Platelet tivity, via an effect on sodium handling. In aggregating ability is also usually raised, and some cases hypertension may be secondary to hypertension is common. Thus major risk factors diabetic kidney disease, although the converse for atherosclerosis are intensified and cerebro- may also be true (see Chapter 4, p. 213). vascular disease, stroke, IHD and peripheral vas- Alternatively, it may be that a third, as yet cular disease are common. Macroangiopathy also unknown, independent factor first causes insulin contributes to kidney disease. resistance, which then leads to both type 2 diabetes and hypertension. Hyperinsulinaemia could then be a common link in the Other mechanisms vascular complications of both diabetes and As illustrated in Figure 9.6, other complications of hypertension. diabetes occur, the pathogenesis of which remain The UKPDS (1998) found that rigorous control obscure. Moreover, different complications of blood pressure in diabetes reduced complica- may be inter-related or coexistent. Neuropathy tions. However, prolonged therapy with two may result partly from direct neuronal damage common antihypertensive agents, thiazide and partly from impaired blood supply to the diuretics and beta-blockers, while effectively nerve sheaths. Microangiopathy may result lowering blood pressure, can also lead to glucose partly from glycation, partly from polyol accu- intolerance or even overt diabetes. For this mulation and partly from hyperinsulinaemia. reason beta-blockers are not recommended as Once nephropathy is established, it promotes first-line treatment for hypertension in diabetes, hypertension and vascular disease. and extra care is needed with both.
  21. 21. Complications 601 Clinical consequences Renal. Diabetic nephropathy is the cause of death in about 25% of type 1 diabetes. Predomi- Almost any system in the body may be affected nantly a form of sclerosis of the glomerular base- by diabetic complications, which is why diabetes ment membrane, it develops very slowly and so is regarded as a multisystem disease (Table 9.13). most commonly occurs in type 1 patients, up to 40% of whom may be affected. The increased Eyes. Diabetes is the most common cause of glomerular filtration rate (‘hyperfiltration’) in acquired blindness in developed countries. After early diabetes, which is due to hypertension and 30 years of diabetes, about 50% of patients have to the osmotic loading of hyperglycaemia, may some degree of retinopathy, and up to 10% overload renal capillaries. Nephropathy is become blind. The blindness is due to small- heralded by microalbuminuria, with increasing vessel damage in the retina, with dilatation, proteinuria frequently progressing to end-stage haemorrhage, infarction and ultimately exces- renal failure, associated with worsening hyper- sive proliferation of new vessels that project tension. Diabetic nephropathy is one of the most into the vitreous humour (neovascularization). common causes of chronic renal failure, with Retinopathy is frequently associated with people with diabetes comprising about 15% of nephropathy. People with diabetes also have an the caseload of UK renal replacement therapy increased incidence of glaucoma and cataract. units. Renal decline is hastened by inadequate or tardy treatment of associated hypertension. Nervous system. Diabetic neuropathy may affect any part of the peripheral nervous system, Cardiovascular. About half of diabetic deaths but most commonly starts with the peripheral are from the consequences of macroangiopathy. sensory nerves, causing tingling and numbness People with diabetes have a twofold greater risk of (paraesthesias), loss of vibration sense or the stroke and a fivefold greater risk of MI compared sense of balance and limb position. It may inter- with matched non-diabetic subjects. Peripheral fere with the ability of blind people with vascular disease is also common, with a 50-fold diabetes in reading Braille. Autonomic higher risk of peripheral gangrene. Some patients neuropathy is potentially devastating because undergo progressively extensive amputation; it can seriously disturb cardiovascular, gastro- usually the lower limbs (especially the feet; see intestinal or genitourinary function, causing below) are affected, but fingers are also at risk. numerous symptoms; postural hypotension and Hypertension is often associated with diabetes. impotence are common. Voluntary motor nerves Up to 50% of type 1 patients have it, and it is are less commonly affected. probably secondary to nephropathy. About a Table 9.13 Clinical consequences of diabetic complications System Clinical features Eyes Retinopathy, glaucoma, cataract; blindness Nerves Sensory, autonomic and motor defects Renal Glomerulosclerosis; chronic renal failure Cardiovascular Ischaemic heart disease (angina, MI), peripheral vascular disease, stroke; cardiomyopathy; congestive heart failure Locomotor Slow-healing peripheral lesions; ‘the diabetic foot’; amputations; joint stiffness Immune Increased susceptibility to infection MI, myocardial infarction.