Proinsulin processing in the regulated and the constitutive secretory pathway

Proinsulin is converted to insulin in beta-cell granules. Conversion involves endoproteolytic cleavage at the two pairs of basic residues linking the insulin A- and B-chains to C-peptide. The sequence of events leading to complete conversion differs from one proinsulin species to the next. In man, the structure of the proinsulin molecule is such as to favour cleavage at the B-chain/C-peptide junction leading to the generation of des-31,32 split proinsulin as the predominant, naturally occurring conversion intermediate. Under normal circumstances, proinsulin conversion is largely completed before secretion, and neither the intact prohormone nor conversion intermediates are thus encountered in large quantities in the circulation. In some pathological situations, including non-insulin-dependent diabetes, insulinoma and familial hyperproinsulinaemia, unusually high ratios of des-31,32 split proinsulin and/or proinsulin to insulin have been reported. As we understand the biochemistry of proinsulin conversion in increasingly fine molecular detail, it should become possible to make use of such unusual ratios to provide insight into lesions underlying altered beta-cell function in disease states.