Insulin and glucagon

The islets of Langerhans

How glucose triggers insulin release

1. Glucose enters beta cells through GLUT2 (low affinity, so uptake tracks blood glucose). 2. Glucokinase phosphorylates it (the glucose sensor); glycolysis and oxidation raise ATP. 3. ATP closes ATP-sensitive K⁺ channels (K-ATP). 4. The cell depolarises and voltage-gated Ca²⁺ channels open. 5. Ca²⁺ entry triggers exocytosis of insulin granules.

• Sulphonylureas (gliclazide, glibenclamide) close K-ATP channels directly, releasing insulin regardless of glucose, so they cause hypoglycaemia. Diazoxide opens the channels (insulinoma, congenital hyperinsulinism).
• Hypokalaemia hyperpolarises beta cells and reduces insulin release; this is the main reason high-dose thiazides raise glucose.
• Insulin release is inhibited by: somatostatin, adrenaline and noradrenaline (alpha-2), hypokalaemia, diazoxide, fasting. Stimulated by: glucose, amino acids, incretins, vagal (ACh) activity, glucagon, sulphonylureas.
• Release is biphasic; the rapid first phase is lost early in type 2 diabetes.
• Incretins: oral glucose releases more insulin than the same IV glucose because gut GLP-1 (L cells) and GIP amplify release. DPP-4 destroys them within minutes. Sitagliptin inhibits DPP-4; semaglutide and other GLP-1 agonists also slow gastric emptying and act centrally on satiety, causing fullness, nausea and weight loss. Their insulin effect is glucose-dependent, so hypoglycaemia is uncommon alone.
• Proinsulin is cleaved into insulin and C-peptide in equal amounts. C-peptide reveals endogenous secretion: high in insulinoma and sulphonylurea misuse, low when hypoglycaemia comes from injected insulin.
• Rebound hypoglycaemia after phaeochromocytoma removal: catecholamines had suppressed insulin (alpha-2); when they fall abruptly, insulin rebounds while hepatic glucose output drops.

Insulin actions (the fed-state hormone)

• Insulin-dependent transporter: GLUT4 (skeletal and cardiac muscle, adipose tissue). Brain (GLUT1, GLUT3), red cells (GLUT1), liver, kidney and beta cells (GLUT2) take up glucose without insulin.
• Insulin acts through a receptor tyrosine kinase (IRS, PI3K).
• Insulin is confined largely to the ECF: 0.1 g given, with plasma concentration 1 mg/100 mL after mixing, gives a distribution volume of 100 mg ÷ 0.01 mg/mL = 10 L.
• Acanthosis nigricans: in insulin resistance very high insulin stimulates IGF-1 receptors on keratinocytes and fibroblasts, giving velvety dark skin in the neck and axillae (obese adolescents, PCOS). In a thin older adult losing weight, exclude gastric cancer.

Glucagon (the fasting hormone)

• Acts mainly on the liver through Gs and cAMP: glycogenolysis (main action), gluconeogenesis and ketogenesis. It decreases glycogen synthesis, glycolysis and fatty acid synthesis.
• Stimulated by hypoglycaemia, amino acids (protein meal) and sympathetic activity; inhibited by glucose, insulin and somatostatin.
• Glucagon and adrenaline share a liver mechanism: both raise cAMP and stimulate glycogenolysis.
• IM glucagon treats severe hypoglycaemia without IV access; it fails when glycogen is depleted (alcohol, starvation).

Counter-regulation and hypoglycaemia

• As glucose falls: insulin secretion stops, then glucagon and adrenaline rise (minutes), then cortisol and GH (hours).
• Adrenergic symptoms (sweating, tremor, palpitations) come first, then neuroglycopenia (confusion, seizures). Beta-blockers and long-standing diabetes blunt warning symptoms.
• A conscious patient who can swallow (glucose 2.9 mmol/L, 52 mg/dL): 15–20 g fast-acting glucose by mouth, recheck in 10–15 minutes, then a longer-acting carbohydrate. Chocolate is poor (fat slows absorption).
• Dawn phenomenon: early-morning GH and cortisol raise fasting glucose with normal 3 a.m. readings.

Fed and fasting states

• Fed: insulin dominates; glucose stored as glycogen and fat.
• Early fast: liver glycogenolysis (glycogen lasts about 24 hours).
• Prolonged fast: gluconeogenesis from amino acids, lactate and glycerol; ketone bodies rise and the brain adapts to them.
• Ketogenesis: low insulin and high glucagon release fatty acids from fat; in liver mitochondria beta-oxidation produces excess acetyl-CoA, which forms HMG-CoA and then acetoacetate and beta-hydroxybutyrate.

Diabetes mellitus

• Diagnosis (WHO): fasting glucose ≥ 7.0 mmol/L (126 mg/dL), random or 2-hour OGTT ≥ 11.1 mmol/L (200 mg/dL), or HbA1c ≥ 48 mmol/mol (6.5%).
• HbA1c is the test of choice for long-term control (2–3 months), because glucose glycates haemoglobin throughout the red cell's life. It is falsely low when red cells live shorter (sickle cell disease, haemolysis, recent transfusion, thalassaemia major) and falsely high in iron deficiency. Use fructosamine (glycated albumin, about 2–3 weeks) instead.
• Polyuria in hyperglycaemia is osmotic diuresis: glucose above the renal threshold stays in the tubule and holds water.
• Translocational hyponatraemia: glucose 40 mmol/L draws water out of cells, diluting sodium (128 mmol/L) while osmolality is high. Corrected sodium (add about 2.4 mmol/L per 5.5 mmol/L, 100 mg/dL, glucose above normal) may be normal or high.
• Annual foot check with a 10 g monofilament detects lost protective sensation before ulcers form; a hot, swollen, painless foot is Charcot arthropathy.

DKA and HHS

• DKA: absent insulin allows lipolysis and ketogenesis, giving a high anion gap metabolic acidosis, osmotic diuresis, dehydration and Kussmaul breathing. Plasma K⁺ may be high but total body K⁺ is low; insulin drives K⁺ and phosphate into cells, so both fall sharply during treatment (phosphate from 1.6 to 0.4 mmol/L). Treat with fluids, fixed-rate insulin and potassium.
• HHS: older type 2 patients, often after illness (hip fracture). Glucose very high (for example 50 mmol/L) and osmolality above 320 (370 here) with no significant ketosis, because residual insulin is enough to suppress lipolysis in fat, though not to control glucose. Fluid replacement is the first priority; insulin is given cautiously.

Remember Glucose to GLUT2 to glucokinase to ATP, K-ATP closes, Ca²⁺ enters, insulin leaves.

Exam trap Sulphonylureas close K-ATP channels; diazoxide opens them; C-peptide is low with injected insulin.

Exam trap HbA1c is falsely low in haemolysis, sickle cell disease and after transfusion; use fructosamine.

How FCPS asks about this

• Cells secreting glucagon and somatostatin: alpha and delta cells; beta cells are the most numerous.
• Insulin-dependent transporter: GLUT4 in muscle and fat.
• Sitagliptin and semaglutide: DPP-4 inhibition; GLP-1 agonism slowing gastric emptying with central satiety.
• Low HbA1c in sickle cell or transfused thalassaemia: short red cell life; use fructosamine.
• No ketones in HHS: residual insulin suppresses lipolysis.
• Phosphate falls during DKA treatment: insulin drives it into cells.
• Hypoglycaemia after phaeochromocytoma removal: rebound insulin release as catecholamines fall.