proinsuline

Proinsulin is the single-chain precursor of insulin, produced in pancreatic beta cells. It is encoded by the INS gene and begins as preproinsulin, which includes a signal peptide. After entry into the endoplasmic reticulum, the signal peptide is removed to form proinsulin, a compact molecule that contains the B-chain, C-peptide, and A-chain in a contiguous sequence. Proinsulin folds and forms two disulfide bonds that connect the A and B chains.

In the secretory pathway, proinsulin is trafficked to secretory granules, where processing occurs. Two endoproteases, prohormone convertases PC1/3 and PC2, cleave proinsulin at the junctions between the B and C-peptide and between the C-peptide and the A-chain. Carboxypeptidase E then trims the resulting basic residues, yielding mature insulin (composed of the A and B chains linked by disulfide bonds) and free C-peptide. Insulin and C-peptide are co-secreted from beta cells in equimolar amounts in response to rising blood glucose and other secretagogues.

Proinsulin itself has relatively little direct insulin receptor activity; the biological effects are mainly due to mature insulin. Nonetheless, circulating proinsulin can be measured in some clinical settings. Elevated proinsulin levels or an increased proinsulin-to-insulin ratio can indicate beta-cell dysfunction and are sometimes observed in type 2 diabetes or impaired glucose tolerance. Genetic mutations in INS can disrupt proinsulin folding or processing, causing neonatal or familial diabetes. Proinsulin testing, alongside insulin and C-peptide measurements, helps assess beta-cell function and insulin secretion.