Insulin

Insulin is a peptide hormone composed of two polypeptide chains totalling 51 amino acids (5.8 kDa): A chain of 21 residues and B chain of 30 residues, linked by two intermolecular disulfide bridges (A7-B7 and A20-B19) and one intramolecular disulfide bridge (A6-A11). It is secreted by β-cells of pancreatic islets of Langerhans in response to postprandial glycaemic elevation, following a biphasic cycle (rapid preformed secretion then slow neosynthesis).

Biosynthesis. Insulin is synthesised as preproinsulin (110 aa) in the endoplasmic reticulum, cleaved into proinsulin (86 aa, B chain + connecting C-peptide + A chain) then into mature insulin + C-peptide (31 aa) by proprotein convertases PC1/3 and PC2 and carboxypeptidase E in secretory granules. It is stored as hexameric crystalline form coordinating 2 Zn²⁺ ions, then released by exocytosis.

Mechanism of action. Insulin binds the insulin receptor (IR, transmembrane tyrosine kinase α₂β₂), inducing autophosphorylation and activation of IRS-1/2/4 substrates → PI3K/AKT (GLUT4 translocation, glycogen synthesis via GSK3, protein synthesis via mTOR, lipolysis inhibition), Ras/MAPK (mitogenic effects). Insulin exists as several therapeutic analogues: rapid (lispro, aspart, glulisine), intermediate (NPH), long (glargine, detemir, degludec) with C-terminal modifications and acylation to modulate PK.

Reference and research. Discovered by Banting and Best (1921), insulin was the first therapeutic peptide hormone (1922) and the first fully sequenced (Sanger 1955, Nobel Prize 1958). It remains a major structural reference in peptide pharmacology, notably for SPPS, native chemical ligation (NCL) and recombinant production (E. coli, yeast) techniques. In research, it is used as positive control, IR assay substrate, and reference for the development of glucagon/GLP-1/insulin hybrid analogues (co-agonists).