Insulin & Glucagon Physiology
Physiology · Endocrine · lean revision notes
Insulin & Glucagon Physiology
The insulin–glucagon axis is the master regulator of fuel homeostasis, switching the body between the fed (anabolic) and fasting (catabolic) states. This topic is a perennial NEET PG favourite, blending pure physiology (receptor signalling, secretion triggers) with high-yield clinical correlations (C-peptide, Somogyi effect, dawn phenomenon, insulin resistance).
Overview: the islets of Langerhans
The endocrine pancreas accounts for only 1–2% of pancreatic mass but is functionally critical. The islets of Langerhans contain four major cell types arranged in a characteristic topography.
| Cell | Proportion | Secretory product | Core function |
|---|---|---|---|
| Beta (β) | ~60–70% (central core) | Insulin, C-peptide, amylin | Anabolic; lowers blood glucose |
| Alpha (α) | ~20% (peripheral) | Glucagon | Catabolic; raises blood glucose |
| Delta (δ) | ~5–10% | Somatostatin | Paracrine inhibition of insulin & glucagon |
| PP / F cell | ~1–2% | Pancreatic polypeptide | Inhibits pancreatic exocrine secretion |
High-yield: Beta cells are in the centre, alpha cells at the periphery, with delta cells interspersed. Somatostatin from delta cells exerts paracrine inhibition on BOTH insulin and glucagon — this is why somatostatinoma causes a triad of diabetes, gallstones (cholelithiasis) and steatorrhoea.
The islets are richly vascularised, and blood flows from the central beta cells outward to alpha and delta cells, allowing insulin to locally regulate glucagon release.
Insulin: structure and biosynthesis
Insulin is a 51-amino-acid polypeptide composed of an A chain (21 aa) and a B chain (30 aa) linked by two interchain disulphide bonds, with a third intrachain disulphide bond in the A chain.
Biosynthesis flow: Preproinsulin (signal peptide removed) → Proinsulin (single chain) → cleavage by prohormone convertases (PC1/3 and PC2) and carboxypeptidase E → mature Insulin + C-peptide (connecting peptide), secreted in equimolar amounts.
High-yield: Insulin and C-peptide are co-secreted in a 1:1 molar ratio from the same secretory granule. C-peptide has a longer half-life (~30 min vs ~5–6 min for insulin) and is NOT extracted by the liver on first pass, making it the marker of endogenous beta-cell function.
C-peptide — why it matters clinically
- Distinguishes type 1 from type 2 DM — low/absent C-peptide indicates beta-cell failure (T1DM, end-stage T2DM).
- Factitious hypoglycaemia (surreptitious insulin injection) → HIGH insulin but LOW C-peptide (exogenous insulin has no C-peptide). Contrast with insulinoma and sulphonylurea abuse, where both insulin and C-peptide are HIGH.
- Crystalline zinc stabilises insulin storage as hexamers in granules.
| Cause of hypoglycaemia | Insulin | C-peptide | Proinsulin | Sulphonylurea screen |
|---|---|---|---|---|
| Insulinoma | High | High | High | Negative |
| Sulphonylurea abuse | High | High | Normal/high | Positive |
| Exogenous insulin (factitious) | Very high | Low/suppressed | Low | Negative |
Mechanism of insulin secretion
This is the single most tested mechanism in this topic.
Stepwise (glucose-stimulated insulin secretion, GSIS):
- Glucose enters the beta cell via GLUT-2 (a high-Km, insulin-independent transporter — acts as the glucose sensor).
- Glucokinase (hexokinase IV, the rate-limiting "glucose sensor" enzyme) phosphorylates glucose.
- Glycolysis and oxidative metabolism raise the intracellular ATP/ADP ratio.
- Rising ATP closes the ATP-sensitive K⁺ channel (K_ATP) — composed of Kir6.2 (pore) + SUR1 (sulphonylurea receptor).
- K⁺ efflux stops → membrane depolarises.
- Depolarisation opens voltage-gated Ca²⁺ channels → Ca²⁺ influx.
- Rise in intracellular Ca²⁺ triggers exocytosis of insulin granules.
High-yield: GLUT-2 + glucokinase form the beta-cell "glucose sensor." Sulphonylureas and meglitinides bind SUR1 and close the K_ATP channel directly, bypassing glucose metabolism — hence they cause hypoglycaemia even when fasting. Diazoxide does the OPPOSITE (opens K_ATP) → inhibits insulin release → used in insulinoma.
Mnemonic for GSIS: "Glucose Goes Killing Voltage, Calcium Comes" — GLUT2 → Glucokinase → K_ATP closes → Voltage-gated Ca²⁺ opens → Calcium-mediated exocytosis.
Insulin secretion is biphasic
- First phase: rapid spike (~minutes) from pre-formed, docked granules — lost early in T2DM.
- Second phase: sustained release from newly synthesised insulin.
Triggers and modulators of insulin secretion
| Stimulators ↑ | Inhibitors ↓ |
|---|---|
| Glucose (most potent), mannose | Somatostatin |
| Amino acids (arginine, leucine) | Adrenaline / noradrenaline (α₂ effect) |
| GLP-1, GIP (incretins) | Sympathetic stimulation |
| Glucagon, GIP, secretin, CCK (gut hormones) | Diazoxide, thiazides, phenytoin |
| Vagal (parasympathetic, muscarinic) | Leptin |
| Sulphonylureas, meglitinides | Chronic hyperglycaemia (glucotoxicity) |
| β-keto acids, free fatty acids (acute) | Galanin |
High-yield: Catecholamines inhibit insulin via α₂-adrenergic receptors (decreasing cAMP). This is why stress, shock and phaeochromocytoma cause hyperglycaemia. β₂ stimulation, by contrast, can increase insulin — but the α₂ effect dominates physiologically.
The incretin effect
Oral glucose evokes far more insulin secretion than the same dose given intravenously — the incretin effect — because the gut releases incretin hormones.
- GLP-1 (glucagon-like peptide-1) — from intestinal L cells (ileum/colon).
- GIP (glucose-dependent insulinotropic peptide) — from K cells (duodenum/jejunum).
Both act in a glucose-dependent manner (only stimulate insulin when glucose is high → low hypoglycaemia risk). They are degraded by DPP-4 (dipeptidyl peptidase-4).
High-yield: GLP-1 effects = ↑ glucose-dependent insulin, ↓ glucagon, ↓ gastric emptying, ↑ satiety (weight loss). This underlies GLP-1 agonists (semaglutide, liraglutide) and DPP-4 inhibitors (sitagliptin, vildagliptin — the "gliptins"). The incretin effect is BLUNTED in T2DM.
Insulin receptor and signal transduction
The insulin receptor is a receptor tyrosine kinase (RTK) — a heterotetramer of two extracellular α-subunits (bind insulin) and two transmembrane β-subunits (intrinsic tyrosine kinase activity).
Signalling flow: Insulin binds α-subunits → autophosphorylation of β-subunit tyrosines → recruitment & phosphorylation of IRS-1/IRS-2 (insulin receptor substrates) → activation of PI3K → generation of PIP₃ → activation of Akt (PKB).
The two main downstream arms:
- PI3K–Akt pathway (metabolic): GLUT-4 translocation, glycogen synthesis (inhibits GSK-3), lipogenesis, protein synthesis, suppression of gluconeogenesis. This is the principal metabolic pathway.
- RAS–MAPK pathway (mitogenic): cell growth, proliferation, gene expression.
High-yield: Insulin causes GLUT-4 vesicles to translocate to the cell membrane in skeletal muscle and adipose tissue via the PI3K–Akt pathway. GLUT-4 is the only insulin-dependent transporter most relevant for exams.
GLUT transporters — must-know table
| Transporter | Location | Insulin-dependent? | Notes |
|---|---|---|---|
| GLUT-1 | RBCs, brain, BBB, placenta | No | Basal uptake |
| GLUT-2 | Liver, beta cell, kidney, gut | No | Bidirectional, glucose sensor (high Km) |
| GLUT-3 | Neurons, placenta | No | High affinity (low Km) |
| GLUT-4 | Skeletal/cardiac muscle, adipose | Yes | Insulin-responsive |
| GLUT-5 | Intestine, sperm | No | Fructose transporter |
| SGLT-1/2 | Gut / proximal tubule | No (Na⁺-coupled) | SGLT-2 = gliflozin target |
Metabolic (anabolic) effects of insulin
Insulin is the hormone of "feast" — it promotes fuel storage. Organise by tissue:
Liver:
- ↑ Glycogen synthesis (activates glycogen synthase, inhibits glycogen phosphorylase).
- ↓ Gluconeogenesis and ↓ glycogenolysis.
- ↑ Lipogenesis (fatty acid synthesis); ↑ VLDL.
- ↓ Ketogenesis.
Skeletal muscle:
- ↑ Glucose uptake (GLUT-4) and glycogen synthesis.
- ↑ Amino acid uptake and protein synthesis; ↓ proteolysis.
- Promotes K⁺ entry into cells (via Na⁺/K⁺-ATPase stimulation).
Adipose tissue:
- ↑ Glucose uptake (GLUT-4); ↑ triglyceride storage.
- ↑ Lipoprotein lipase (clears circulating TG).
- Inhibits hormone-sensitive lipase → ↓ lipolysis → ↓ free fatty acids → ↓ ketogenesis.
High-yield: Insulin drives potassium intracellularly — exploited in the treatment of hyperkalaemia (insulin + dextrose). Conversely, insulin deficiency (DKA) causes a paradoxical hyperkalaemia despite total-body K⁺ depletion. Insulin inhibits hormone-sensitive lipase; its absence in T1DM → unrestrained lipolysis → ketoacidosis.
Summary mnemonic — insulin "builds up" (anabolic): glycogen ↑, protein ↑, fat ↑, K⁺ in, glucose down.
Glucagon: the counter-regulatory hormone
Glucagon is a 29-amino-acid single-chain peptide from alpha cells. It is the dominant hormone of the fasting state and acts almost exclusively on the liver via a Gs-coupled GPCR → adenylyl cyclase → ↑ cAMP → PKA pathway.
Actions of glucagon:
- ↑ Glycogenolysis (its fastest, most important action).
- ↑ Gluconeogenesis.
- ↑ Ketogenesis and lipolysis.
- ↑ Amino acid uptake by liver (ureagenesis).
- Net effect: raises blood glucose.
High-yield: Glucagon acts predominantly on the LIVER (hepatocytes have abundant glucagon receptors; muscle has none). Hence muscle glycogen cannot directly raise blood glucose because muscle lacks glucose-6-phosphatase and glucagon receptors.
Regulation of glucagon
| Stimulators of glucagon ↑ | Inhibitors of glucagon ↓ |
|---|---|
| Hypoglycaemia (main trigger) | Hyperglycaemia |
| Amino acids (arginine, alanine) | Insulin (paracrine) |
| Sympathetic stimulation, adrenaline | Somatostatin |
| CCK, gastrin, cortisol | GLP-1, free fatty acids |
| Exercise, stress, fasting | Ketones |
High-yield: A protein-rich meal stimulates BOTH insulin and glucagon (amino acids trigger both). The glucagon rise prevents the hypoglycaemia that insulin alone would cause after a pure-protein meal. This is a classic NEET PG concept.
Insulin : glucagon ratio
The insulin/glucagon ratio dictates the metabolic state, not absolute levels:
- High ratio (fed): anabolic — glycogenesis, lipogenesis.
- Low ratio (fasting/starvation/DKA): catabolic — glycogenolysis, gluconeogenesis, ketogenesis.
Counter-regulatory hormones (anti-insulin)
When glucose falls, the body defends in a hierarchy. The first hormonal response is suppression of insulin; the first counter-regulatory hormones released are glucagon and adrenaline.
Defence sequence against hypoglycaemia: Glucose ↓ → insulin secretion ↓ → glucagon ↑ (primary defence) → adrenaline ↑ → (if prolonged) cortisol & growth hormone ↑.
High-yield: Glucagon and adrenaline are the rapid counter-regulators. In long-standing T1DM, glucagon response is lost first, then the adrenaline response → hypoglycaemia unawareness. Cortisol and GH act over hours, mainly in prolonged fasting.
Clinical applications & special phenomena
Somogyi effect vs dawn phenomenon
Both cause morning (fasting) hyperglycaemia but mechanisms — and management — differ.
| Feature | Somogyi effect | Dawn phenomenon |
|---|---|---|
| Mechanism | Rebound hyperglycaemia after nocturnal hypoglycaemia (counter-regulatory surge) | Early-morning surge of GH/cortisol → ↑ gluconeogenesis |
| 3 AM glucose | LOW | Normal or high |
| Cause | Too much night-time insulin | Normal circadian hormone rhythm |
| Management | Decrease evening insulin / add bedtime snack | Increase or shift evening insulin |
High-yield: Check the 3 AM blood glucose to differentiate. Low at 3 AM = Somogyi (reduce insulin); normal/high = dawn phenomenon (increase/adjust insulin). The Somogyi effect is increasingly considered rare/controversial, but remains a favourite MCQ.
Insulin resistance — mechanisms
Insulin resistance is the hallmark of T2DM and metabolic syndrome: a normal insulin level produces a subnormal biological response.
Mechanisms (mostly post-receptor):
- Serine phosphorylation of IRS-1 (instead of tyrosine) → impaired PI3K signalling. Driven by TNF-α, free fatty acids, and inflammatory kinases (JNK, IKKβ).
- ↓ GLUT-4 translocation in muscle and fat.
- Hepatic resistance → unsuppressed gluconeogenesis → fasting hyperglycaemia.
- Adipokine imbalance: ↑ resistin, ↑ leptin (with leptin resistance), ↓ adiponectin (insulin-sensitising).
- Lipotoxicity and ectopic fat (visceral, hepatic).
High-yield: The earliest molecular lesion in T2DM insulin resistance is post-receptor (serine phosphorylation of IRS-1, impaired PI3K-Akt), not receptor down-regulation. Acanthosis nigricans is the classic skin marker of hyperinsulinaemia/insulin resistance.
Other clinical correlates
- Amylin (IAPP): co-secreted with insulin; slows gastric emptying, suppresses glucagon. Amyloid deposits in T2DM islets. Pramlintide is the analogue.
- Insulinoma: Whipple's triad (symptoms of hypoglycaemia + low plasma glucose + relief with glucose). High insulin, high C-peptide.
- Metformin works mainly by reducing hepatic gluconeogenesis (activates AMPK); it is not an insulin secretagogue → does not cause hypoglycaemia alone.
Key differentials / commonly confused concepts
- GLUT-2 vs GLUT-4: GLUT-2 = sensor (liver/beta cell, insulin-independent); GLUT-4 = effector (muscle/fat, insulin-dependent).
- Glucokinase vs hexokinase: glucokinase (liver/beta cell) has high Km, not inhibited by product, acts as sensor; hexokinase has low Km, product-inhibited.
- Insulin receptor (RTK) vs glucagon receptor (GPCR/cAMP): opposite signalling families.
- Sulphonylurea (closes K_ATP) vs diazoxide (opens K_ATP): opposite effects on insulin release.
Recently asked / exam angle
- Mechanism of glucose-stimulated insulin secretion — sequence of GLUT-2 → glucokinase → ATP → K_ATP closure → Ca²⁺ influx (repeatedly asked; often as "which channel closes?").
- C-peptide interpretation in factitious hypoglycaemia vs insulinoma vs sulphonylurea abuse.
- Insulin receptor is a tyrosine kinase signalling via IRS-1 → PI3K → Akt; GLUT-4 translocation.
- Glucagon acts on the liver via cAMP; predominant action = glycogenolysis.
- Catecholamines inhibit insulin via α₂ receptors.
- Differentiation of Somogyi effect vs dawn phenomenon using 3 AM glucose.
- Incretins (GLP-1 from L cells, GIP from K cells), DPP-4 degradation, and glucose-dependent action.
- Insulin and potassium — use in hyperkalaemia; paradoxical hyperkalaemia in DKA.
- First counter-regulatory hormone to hypoglycaemia = glucagon (then adrenaline).
- Somatostatinoma triad; diazoxide use in insulinoma.
Rapid revision
- Beta cells central, alpha peripheral; somatostatin (delta) inhibits both via paracrine action.
- Insulin & C-peptide secreted 1:1; C-peptide marks endogenous secretion (low in exogenous/factitious insulin).
- Beta-cell glucose sensor = GLUT-2 + glucokinase; ATP closes K_ATP (Kir6.2/SUR1), Ca²⁺ enters → exocytosis.
- Sulphonylureas close K_ATP (secretagogue); diazoxide opens it (used in insulinoma).
- Insulin receptor = tyrosine kinase → IRS-1 → PI3K → Akt (metabolic) and RAS–MAPK (growth).
- GLUT-4 (muscle, fat) is the only major insulin-dependent transporter; GLUT-5 carries fructose.
- Insulin is anabolic: ↑ glycogen, fat, protein; drives K⁺ into cells; inhibits hormone-sensitive lipase.
- Glucagon acts on liver via cAMP; chief action = glycogenolysis, then gluconeogenesis/ketogenesis.
- Catecholamines inhibit insulin via α₂ receptors → stress hyperglycaemia.
- Incretins: GLP-1 (L cells), GIP (K cells), degraded by DPP-4, glucose-dependent → low hypoglycaemia risk.
- Somogyi = low 3 AM glucose, reduce insulin; dawn phenomenon = GH/cortisol surge, increase/adjust insulin.
- T2DM insulin resistance is post-receptor (serine phosphorylation of IRS-1, ↓ adiponectin); glucagon is the first counter-regulatory hormone to hypoglycaemia.