Describe the source, synthesis, actions and regulation of insulin. Add a note on glucagon.

Source and Structure

• 51 amino acids — A chain (21) + B chain (30), joined by 2 disulphide bridges. MW 5808
• Synthesis — preproinsulin → proinsulin → insulin + C-peptide, in equimolar amounts
• C-peptide has no hormonal action, but its measurement indicates endogenous insulin secretion — useful to distinguish factitious hypoglycaemia from an insulinoma
• Half-life 5–6 minutes; degraded by insulinase in liver and kidney

Mechanism of Secretion

Glucose enters β cell via GLUT-2 → Phosphorylated by glucokinase (the glucose sensor) → Metabolised → ↑ ATP/ADP ratio → ATP-sensitive K+ channel closes → Membrane depolarises → Voltage-gated Ca2+ channels open → ↑ Cytosolic Ca2+ → Exocytosis of insulin granules

• Sulfonylureas (glibenclamide) close the same K+ channel → stimulate insulin release
• Secretion is biphasic — a rapid first phase from stored granules, then a sustained second phase from newly synthesised hormone. The first phase is lost early in type 2 diabetes

Regulation of Secretion

Mechanism of Action

• Receptor is a tetramer (2α + 2β) with intrinsic tyrosine kinase activity
• Insulin binds the α subunits → β subunits autophosphorylate → phosphorylate IRS proteins → downstream cascade
• Chief metabolic effect — translocation of GLUT-4 from intracellular vesicles to the cell membrane in muscle and adipose tissue

Actions of Insulin

• Insulin is the body's only hypoglycaemic hormone; glucagon, cortisol, growth hormone and adrenaline all oppose it
• It is fundamentally the hormone of the fed state — it promotes storage of all three foodstuffs

Glucagon — the Counter-regulator

Other Hormones Affecting Blood Glucose

• The four counter-regulatory hormones — glucagon, adrenaline, cortisol and GH — defend against hypoglycaemia. Glucagon and adrenaline act within minutes; cortisol and GH over hours

Applied Aspects

• Type 1 diabetes — autoimmune β cell destruction → absolute deficiency; ketosis-prone; insulin is essential
• Type 2 diabetes — insulin resistance with relative deficiency; associated with obesity; ketosis is uncommon
• Diabetic ketoacidosis — unopposed lipolysis → ketone bodies → metabolic acidosis with Kussmaul breathing and a fruity breath
• Insulinoma — Whipple triad: hypoglycaemic symptoms, low blood glucose, relief with glucose. C-peptide is high
• Insulin + dextrose is standard emergency treatment for hyperkalaemia