HYPOGLYCEMIA - OUTLINE• Drugs asso. with hypoglycemia• Hyperinsulinemic hypoglycemia – D/D• Endogenous hyperinsulinemia – D/D, and, a word on insulinoma• Hypoglycemia in Infancy & Childhood• Diagnostic approach to an adult with hypoglycemia• Management – Emergency management & prevention
DEFINITION“Glucose levels <55mg/dl (<3.0mmol/l) with symptoms that are relieved promptly after the glucose level is raised document hypoglycemia.”• Hypoglycemia is most convincingly documented by, Whipple’s triad, i.e: – Symptoms consistent with hypoglycemia – Low plasma glucose concentration (measured with a precise method) – Relief of symptoms when plasma glucose concentration is increased.
GLUCOSE HOMEOSTASIS – Key roles RESPONSE GLYCEMIC PHYSIOLOGIC EFFECTS ROLE IN GLUCOSE THRESHOLD REGULATION (mg/dl)↓ Insulin 80-85 ↑ Ra (↓ Rd) 1st line of defense (Primary glucose regulatory factor)↑ Glucagon 65-70 ↑ Ra 2nd line of defense (Primary glucose counterreg. factor)↑ Epinephrine 65-70 ↑ Ra ↓ Rc 3rd line of defense (critical when glucagon ↓)↑ Cortisol & GH 65-70 ↑ Ra ↓ Rc Defense against prolonged hypoglycemia, not criticalSymptoms 50-55 Recognition of Prompt behavioral hypoglycemia defense(food ingestion)↓ Cognition < 50 ----- Compromises behavioral defense against hypoglycemia
↓ ARTERIAL GLUCOSE ↓ INSULIN LIVER PANCREAS ↑ GLUCAGON ↑ GLUCOSE PRODUCTION KIDNEY BRAIN ↑ GLUCONEOGENIC PRECURSORS ↑ SYM ADR OUTFLOWPITUITARY MUSCLE FAT ↑GH ↑ ARTERIAL GLUCOSE ACTH ↑E ADR MEDULLA ↓ GLU CLEARANCE INGESTION ADR CORTEX ↑ NE ↑ CORTISOL Post Gn SymN SYMPTOMS ↑ Ach
CLINICAL FEATURES - Symptoms• Neurogenic symptoms: – Sweaty – Hungry – Tingly – Shaky (Tremulous) – Poundy (Palpitations) – Nervy (Anxious/Nervous)• These symptoms are the result of the perception of physiologic changes caused by the ANS discharge (Adr & Chol) triggered by hypoglycemia.
CLINICAL FEATURES - Symptoms• Neuroglycopenic symptoms: – Warm – Weak – Confused/Difficulty thinking – Tired/Drowsy – Faint – Dizzy – Difficulty speaking – Blurred vision• These symptoms are the result of direct CNS glucose deprivation.
CLINICAL FEATURES - Signs• Pallor• Diaphoresis• ↑ PR• ↑ BP• TIA occasionally (Permanent damage is rare)“The magnitude of the responses to hypoglycemia is an inverse function of the nadir plasma glucose concentration rather than the rate of decrease in plasma glucose.” (Ref: William’s T. of Endo 10/e)
MECHANISMS OF HYPOGLYCEMIA• Hypoglycemia implies that the rate of glucose efflux from circulation > rate of glucose influx into circulation. ↑ Efflux ↓ Influx↑ Utilisation ↑ Losses ↓ Endogenous glucose production in the• Exercise • Pregnancy absence of exogenous• Pregnancy • Renal Glycosuria glucose delivery• Sepsis – Most Common cause
MECHANISMS OF HYPOGLYCEMIA Defects causing Hypoglycemia REGULATORY ENZYMATIC SUBSTRATE↑ Secretion of Insulin Primary Failure toOR OR mobilize or↓ Secretion of glucose May result from utilizecounter regulatory hepatic disease gluconeogenichormones substrates
DIAGNOSIS1. Whipple’s triad2. Venous plasma glucose after an overnight fast: • > 70mg/dl (>3.9 mmol/) : Normal • 50 - 70 mg/dl (2.8-3.9 mmol/l) : s/o Hypoglycemia • < 50 mg/dl (<2.8 mmol/l) : => Postabsorptive hypoglycemia3. Postprandial (=Reactive) hypoglycemia: – Diagnosis requires documentation of Whipple’s triad after a mixed meal (low venous plasma concentration post oral glucose load is not sufficient for diagnosis).(Ref: William’s T. of Endo 10/e, Harrison’s Principles of Int Med 17/e, 339:2308)
CLINICAL CLASSIFICATION1. Postabsorptive (=Fasting) Hypoglycemia2. Postprandial (=Reactive) HypoglycemiaSignificance: – Reproducible hypoglycemia in the postabsorptive state, implies the presence of disease and requires diagnostic explanation and treatment. – It may become apparent during the latter part of any interdigestive period (NOT necessarily in the fasting state) esp. post-exercise. – Postprandial (=reactive) hypoglycemia does not usually imply a serious underlying disorder.
CLINICAL CLASSIFICATIONI) POSTABSORPTIVE (=FASTING) HYPOGLYCEMIA:3. HORMONAL DEFICIENCIES: – Cortisol or GH or both – Glucagon or Epinephrine4. NON β CELL TUMORS5. ENDOGENOUS HYPERINSULINISM – Pancreatic β cell disorders – β cell secretagogue (eg: SU) – Autoimmune hypoglycemia (IA, IRA, ? βcell Ab) – ? Ectopic insulin secretion6. HYPOGLYCEMIA OF INFANCY & CHILDHOOD
CLINICAL CLASSIFICATIONII) POSTPRANDIAL (=REACTIVE) HYPOGLYCEMIA:1. Congenital deficiencies of enzymes of carbohydrate metabolism: – Heriditary Fructose intolerance – Galactosemia2. Alimentary Glycosuria: – Post gastrectomy3. Idiopathic (=Functional) postprandial hypoglycemia
HYPOGLYCEMIA IN DMIMPACT & FREQUENCY:• Limiting factor in the glycemic management of DM1. Causes recurrent morbidity in MOST cases of T1DM and MANY with T2DM and is sometimes fatal.2. Precludes maintenance of euglycemia over a lifetime of diabetes and thus full realization of the benefits of glycemic control.3. Causes a vicious cycle of recurrent hypoglycemia by producing hypoglycemia associated autonomic failure – the clinical syndromes of defective glucose counterregulation and of hypoglycemia unawareness.
HYPOGLYCEMIA IN DM – The Burden• T1DM- – Fact of life – Average of 2 episodes of symptomatic hypoglycemia per week and at least one episode of sever, at least temporarily disabling hypoglycemia each year. – Estimated 2-4% of people with T1DM die due to hypoglycemia.• T2DM- – Less frequent than T1DM. – Metformin, TZDs, AGIs, GLP-1 analogues, DDP-4 inhibitors should not cause hypoglycemia, however the risk increases when combined with insulin/SU. – As insulin resistance increases and patients require insulin the risk of hypoglycemia in T2DM approaches that in T1DM.
RISK FACTORS – THE PREMISE“The conventional risk factors for hypoglycemia in diabetesare based on the premise that relative or absolute insulinexcess is the sole determinant of risk.” - Harrison’s Principles of Int Med 17/e, 339:2306“Iatrogenic hypoglycemia in T1DM is the result of theinterplay of therapeutic insulin excess and compromisedglucose counterregulation.” -William’s T. of Endo 10/e
CONVENTIONAL RISK FACTORS• Absolute/Relative Insulin Excess occurs when: – Insulin (or secretogogue) doses are excessive, ill-timed or of the wrong type – The influx of exogenous glucose is reduced (e.g., overnight fast or following missed meals/snacks) – Insulin-independent glucose utilization is increased (e.g., exercise) – Sensitivity to insulin is increased (e.g., improved glycemic control, in the middle of the night, late of the exercise, or with increased fitness or weight loss) – Endogenous glucose production is reduced (e.g., alcohol ingestion) – Insulin clearance is reduced (e.g., renal failure)
COMPROMISED GLUCOSE COUNTERREGULATION• Absolute insulin deficiency (C-peptide negativity): – β cell destruction: No decrease insulin in response to fall in glucose – Unknown: No increase glucagon in response to fall in glucose• H/O severe hypoglycemia/aggressive treatment per se: – Lower glucose goals, low HbA1c – Attenuated autonomic activation & symptoms in response to fall in glucose.
DEFECTIVE GLUCOSE COUNTERREGULATION• Failure of ALL 3 lines of defense.• Result of antecedent iatrogenic hypoglycemia• Glycemic threshold is shifted to lower plasma glucose concentrations.• 25x or more risk of sever iatrogenic hypoglycemia during aggressive glycemic therapy . No ↓ Insulin ↓ Glucose No ↑ Glucagon ↑ Glucose No ↑ Epinephrine
HYPOGLYCEMIA UNAWARENESS• Caused by the attenuated sympathoadrenal response (largely the ↓ sympathetic neural response) to hypoglycemia.• Characterised by the loss of warning adrenergic & cholinergic symptoms that previously allowed the patient to recognise developing hypoglycemia ad therefore abort the episode by ingesting carbohydrates.• 6x increased risk of severe iatrogenic hypoglycemia during aggressive treatment .
ADDITIONAL RISK FACTORS – T1DM1. Insulin deficiency that indicates that insulin levels will not decrease and glucagon levels will not increase as plasma glucose falls2. A h/o severe hypoglycemia or of hypoglycemia unawareness, implying recent antecedent hypoglycemia, that indicates that the sympathoadrenal response will be attenuated; and3. Lower HbA1c levels or lower glycemic goals that, all other factors being equal, increase the probability of recent antecedent hypoglycemia.
HYPOGLYCEMIA IN T2DM THERAPY N HBA1C % ANY % MAJOR HYPO HYPODiet 379 8.0 3.0 0.2Sulphonyl urea 922 7.1 45.0 3.3Insulin 689 7.1 76.0 11.2Diet 297 8.2 2.8 0.4Metformin 251 7.4 17.6 2.4 Ref: UKPDS, Diabetes 1995-44-1249-1258
DRUGS CAUSING HYPOGLYCEMIAESTABLISHED DRUGS: DISORDER DRUG DM Insulin, SU, other secretogogues, metformin, alcohol Infection Pentamidine, Quinine, Sulphonamides Arrhythmias Quinidine, dispyramide, cibenzoline Pain Acetylsalicylic acid
ENDOGENOUS HYPERINSULINEMIA• Hypoglycemia related to endogenous hyperinsulinemia can be caused by- – A primary pancreatic islet (β) cell disorder, typically a β cell tumour (insulinoma), sometimes multiple insulinomas, or, esp. in infants/young children, a functional β cell disorder with β cell hyperplasia or without an anatomic correlate. – A β cell secretogogue, often a SU, theoritically a β cell stimulating antibody. – An antibody to insulin – Ectopic insulin secretion (rare).
ENDOGENOUS HYPERINSULINEMIA• Fundamental pathophysiologic feature of endogenous hyperinsulinemia caused due to a primary β cell disorder or an insulin secretogogue is failure of insulin secretion to fall to very low levels during hypoglycemia.• Critical diagnostic findings: – Plasma insulin ≥3 uU/ml – Plasma C-Peptide concentration ≥ 0.6 ng/ml – Plasma proinsulin concentration ≥ 5.0 pmol/l, when the plasma glucose concentration is < 55 mg/dl with symptoms of hypoglycemia.
INSULINOMA• Uncommon, 1/250,000; > 90% benign, treatable cause of potentially fatal hypoglycemia.• Median age of presentation – 50 yrs (sporadic cases), third decade in MEN 1.• Symptoms: – Various combinations of diplopia, blurred vision, sweating, palpitations or weakness: 85% – Confusion or abnormal behaviour: 80% – Unconsciousness or amnesia: 53% – Grand mal seizures: 12%
HYPOGLYCEMIA IN INFANCY/CHILDHOOD3. Enzyme defects: – CARBOHYDRATE METABOLISM : • Glycogen storage disease Types I / II/ VI • Glycogen synthase deficiency • Fructose 1,6 bis phosphatase deficiency • Fructose 1-phosphate – aldolase deficiency • Gal 1-phosphate – uridyl transferase deficiency
HYPOGLYCEMIA IN INFANCY/CHILDHOOD3. Enzyme defects: – PROTEIN METABOLISM : • Branched chain α ketoacid dehydrogenase complex deficiency – FAT METABOLISM : • FA oxidation defects induding deficiencies in the carnitine cycle • β – oxidation spiral defects • ETC defects • Ketogenesis sequence defects
NEONATAL HYPOGLYCEMIADiagnostic Criteria (Cornblath et al): – < 2.5 mmol/l (<45mg/dl) in infants with clinical manifestations compatible with hypoglycemia, and, – <2.0 mmol/l (<30mg/dl) in infants at risk for hypoglycemia
TREATMENT• Oral treatment with glucose tablets or glucose containing fluids, candy or food is appropriate if the patient is able & willing to take these.• Initial dose = 20 g of glucose• Unable to take oral foods parenteral therapy• IV glucose 25 g bolus followed by infusion guided by serial plasma glucose measurements.• Inj.Glucagon 0.1 mg sc/im can be used esp in T1DM. (it has no role in alcohol induced hypoglycemia)• Eat ASAP restore glycogen stores.
PREVENTION• Identifying & addressing the cause• Encouraging SMBG by patient• Education & empowerment of patient• Flexible insulin or OAD regimens• Rational, individual glycemic goals• Ongoing professional guidance & support