proinsulintoinsulin

Proinsulin is the single-chain precursor of insulin, produced by pancreatic beta cells from the INS gene. It is synthesized as preproinsulin, which includes an N-terminal signal peptide. The signal peptide is removed in the endoplasmic reticulum to form proinsulin, which folds and forms disulfide bonds before being packaged into secretory granules.

In secretory granules, proinsulin is cleaved by specific endopeptidases, primarily PC1/3 and PC2, with the help of carboxypeptidase E. These enzymes sequentially remove the C-peptide to produce mature insulin, consisting of the A and B chains linked by two disulfide bonds, along with a free C-peptide. Mature insulin and C-peptide are co-secreted in equimolar amounts.

Biological activity differs among the products. Proinsulin has much lower affinity for the insulin receptor than insulin, so it is largely inactive in glucose regulation. Insulin is the primary hormone controlling blood glucose, while C-peptide, though not required for insulin’s action, is used clinically as a biomarker of endogenous insulin production.

Clinical relevance extends to the proinsulin-to-insulin ratio, which can reflect beta-cell processing efficiency. Elevated proinsulin or an increased ratio is often observed in beta-cell dysfunction, such as type 2 diabetes or insulin resistance, and in some insulin-secreting tumors. Measurements of proinsulin and C-peptide can aid in distinguishing endogenous insulin production from exogenous insulin use and in assessing remaining beta-cell function.

In summary, the maturation of proinsulin to insulin is a tightly regulated process essential for proper insulin action and for informative clinical assessment of pancreatic beta-cell function.