WHAT BETA-CELL DEFECT COULD LEAD TO HYPERPROINSULINEMIA IN NIDDM - SOME CLUES FROM RECENT ADVANCES MADE IN UNDERSTANDING THE PROINSULIN-PROCESSING MECHANISM

Pancreatic beta-cell dysfunction is a characteristic of non-insulin-de pendent diabetes mellitus (NIDDM). An aspect of this dysfunction is th at an increased proportion of proinsulin is secreted, but an actual be ta-cell defect that leads to hyperproinsulinemia is unknown. Neverthel ess, an impairment in beta-cell proinsulin conversion mechanism has be en suggested as the most likely cause. Insulin is produced from its pr ecursor molecule, proinsulin, by limited proteolytic cleavage at two d ibasic sequences (Arg31, Arg32 and Lys64 , Arg65). Two endopeptidase a ctivities catalyze this cleavage: PC2 and PC3. PC2 endopeptidase cleav es predominately at Lys64, Arg65, and PC3 endopeptidase cleaves at Arg 31, Arg32. The recent identification and characterization of these end opeptidases has enabled a better understanding of the human proinsulin -processing mechanism. In particular, experimental evidence suggests t hat the majority of human proinsulin processing is sequential. PC3 cle aves proinsulin first to generate a proinsulin conversion intermediate that is the preferred substrate of PC2. Both PC2 and PC3 activities a re influenced by Ca2+ and pH, but the more stringent Ca2+ and pH requi rements of PC3 suggest it as the most likely enzyme to regulate proins ulin conversion, as well as initiate it. When an increased demand is p laced on the proinsulin-processing mechanism by a glucose-stimulated i ncrease hi proinsulin biosynthesis, there is a coordinate increase in PC3 biosynthesis (but not in PC2). This supports PC3 as the key endope ptidase that regulates proinsulin processing. In this perspective, the current concepts of the enzymology and regulation of proinsulin conve rsion at a molecular level are reviewed. Then, several hypothetical po ints of beta-cell dysfunction that might affect the proinsulin-process ing mechanism and lead to hyperproinsulinemia are considered. Because the term NIDDM encompasses a wide variety of different disorders, any one or a combination of these possible points of beta-cell dysfunction could result in hyperproinsulinemia for a certain subset of NIDDM.