proinsulin

Proinsulin is the single-chain precursor of insulin, the key hormone that regulates blood glucose. In humans, it is produced in pancreatic beta cells from the INS gene on chromosome 11. The initial translation product is preproinsulin, which contains a signal peptide that directs it to the secretory pathway; removal of the signal peptide yields proinsulin, a roughly 86‑amino‑acid molecule comprising the B chain, C peptide, and A chain. During maturation, proinsulin folds in the endoplasmic reticulum and forms three disulfide bonds that stabilize its structure.

Processing of proinsulin occurs in the secretory pathway, mainly within the trans-Golgi network and secretory granules. Endopeptidases, specifically prohormone convertases PC1/3 and PC2, cleave at two dibasic sites to remove the C-peptide between the B and A chains. Carboxypeptidase E trims residual basic residues, producing mature insulin, which consists of the A and B chains held together by two interchain disulfide bonds and one intrachain disulfide within the A chain. The C-peptide is released alongside insulin in equimolar amounts, and both are stored in secretory granules until secretion.

Clinical relevance: C-peptide serves as a useful marker of endogenous insulin production because it is released in equal amounts with insulin. The proinsulin-to-insulin ratio and circulating proinsulin levels can reflect beta-cell function and insulin processing efficiency; abnormalities are observed in conditions such as insulin resistance, certain forms of diabetes, and insulinomas. Mutations affecting proinsulin folding or processing can underlie forms of diabetes due to impaired insulin maturation.