Describe the structure, synthesis, secretion and metabolic actions of insulin. Add a note on insulin resistance.

Structure and Synthesis

Preproinsulin (signal peptide + B + C + A) → Signal peptide removed in the endoplasmic reticulum → proinsulin → Cleaved in secretory granules by prohormone convertases → insulin + C-peptide, secreted in equimolar amounts

• Synthesised by β cells of the islets of Langerhans
• Stored as a zinc-containing hexamer
• C-peptide has no hormonal action but is clinically valuable — it has a longer half-life and is not present in injected insulin
• Insulin was the first protein to be sequenced (Sanger, 1955) and the first made by recombinant DNA technology (1982)

Regulation of Secretion

Glucose enters the β cell via GLUT-2 → Phosphorylated by glucokinase — the glucose sensor → Metabolism → ↑ ATP:ADP ratio → ATP-sensitive K+ channel closes → Depolarisation → Voltage-gated Ca2+ channels open → ↑ Intracellular Ca2+ → exocytosis of insulin

• Oral glucose releases more insulin than intravenous glucose at the same blood level — the incretin effect, the basis of GLP-1 agonists and DPP-4 inhibitors
• Secretion is biphasic — a rapid first phase from stored granules, then a sustained second phase. Loss of the first phase is the earliest defect in type 2 diabetes

Mechanism of Action

Insulin binds the insulin receptor — a tetrameric (α2β2) tyrosine kinase → β subunits autophosphorylate → Phosphorylate insulin receptor substrates (IRS-1, IRS-2) → Two arms → PI3-kinase → Akt → GLUT-4 translocation, glycogen synthesis, protein synthesis → map kinase → growth and gene expression

Metabolic Actions

• Insulin is the anabolic hormone — it promotes storage of all three fuels and opposes their release. Every action follows from that principle

Insulin Resistance

• Defined as a subnormal response to a normal or raised insulin concentration
• Mechanisms — post-receptor defects in IRS-1 phosphorylation, reduced GLUT-4 translocation, lipotoxicity from free fatty acids, inflammatory cytokines (TNF-α, IL-6) from adipose tissue
• Causes — obesity (especially central), physical inactivity, pregnancy, stress, steroids, acromegaly, Cushing syndrome, polycystic ovary syndrome
• Acanthosis nigricans is the clinical marker — velvety hyperpigmentation of the neck and axillae

Insulin Preparations and Degradation

• Analogues differ from human insulin by a few amino acids, altering the tendency to form hexamers — rapid analogues dissociate faster, long-acting ones precipitate at tissue pH
• Insulin is degraded by insulinase (insulin-degrading enzyme) in liver and kidney; plasma half-life is only 5–6 minutes
• About 50% is removed on the first pass through the liver, which is why peripheral levels are lower than portal ones
• Renal failure prolongs insulin action → the dose must be reduced, a common cause of hypoglycaemia in diabetic nephropathy

Applied Aspects

• C-peptide distinguishes endogenous from exogenous insulin — high in insulinoma, low or absent in factitious hypoglycaemia from injected insulin. A key forensic and clinical test
• C-peptide also assesses residual β-cell function — absent in established type 1, present in type 2
• Sulfonylureas close the KATP channel, mimicking the effect of ATP; they therefore work only if β cells remain
• Neonatal diabetes from KATP channel mutations responds to oral sulfonylureas rather than insulin — a striking example of mechanism guiding therapy
• Insulin with glucose is standard emergency treatment for hyperkalaemia, exploiting its effect on potassium rather than glucose
• Insulin autoantibodies and receptor antibodies cause rare syndromes of extreme resistance or spontaneous hypoglycaemia
• Lipohypertrophy at injection sites impairs absorption; rotating sites is essential and often neglected
• The insulin receptor belongs to the same family as the IGF-1 receptor, which is why very high insulin levels have growth-promoting effects — as in acanthosis nigricans
• Insulin cannot be given orally — it is a protein and would be digested; inhaled and oral formulations remain limited
• Hypoglycaemia is the limiting factor in insulin therapy and the commonest serious adverse effect of diabetes treatment
• Insulin remains on the WHO essential medicines list, yet access and cost are still major barriers in much of the world