Pancreatic β-cell dysfunction is a characteristic of non-insulin-dependent diabetes mellitus (NIDDM). An aspect of this dysfunction is that an increased proportion of proinsulin is secreted, but an actual β-cell defect that leads to hyperproinsulinemia is unknown. Nevertheless, an impairment in β-cell proinsulin conversion mechanism has been suggested as the most likely cause. Insulin is produced from its precursor molecule, proinsulin, by limited proteolytic cleavage at two dibasic sequences (Arg31, Arg32 and Lys64, Arg65xs). Two endopeptidase activities catalyze this cleavage: PC2 and PC3. PC2 endopeptidase cleaves predominately at Lys64, Arg65, and PC3 endopeptidase cleaves at Arg31, Arg32. The recent identification and characterization of these endopeptidases has enabled a better understanding of the human proinsulin-processing mechanism. In particular, experimental evidence suggests that the majority of human proinsulin processing is sequential. PC3 cleaves proinsulin first to generate a proinsulin conversion intermediate that is the preferred substrate of PC2. Both PC2 and PC3 activities are influenced by Ca2+ and pH, but the more stringent Ca2+ and pH requirements of PC3 suggest it as the most likely enzyme to regulate proinsulin conversion, as well as initiate it. When an increased demand is placed on the proinsulin-processing mechanism by a glucose-stimulated increase in proinsulin biosynthesis, there is a coordinate increase in PC3 biosynthesis (but not in PC2). This supports PC3 as the key endopeptidase that regulates proinsulin processing. In this perspective, the current concepts of the enzymology and regulation of proinsulin conversion at a molecular level are reviewed. Then, several hypothetical points of β-cell dysfunction that might affect the proinsulin-processing 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 β-cell dysfunction could result in hyperproinsulinemia for a certain subset of NIDDM

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