INCREASED SECRETORY DEMAND RATHER THAN A DEFECT IN THE PROINSULIN CONVERSION MECHANISM CAUSES HYPERPROINSULINEMIA IN A GLUCOSE-INFUSION RATMODEL OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS

Hyperproinsulinemia in non-insulin-dependent diabetes mellitus (NIDDM) is due to an increased release of proinsulin from pancreatic beta cel ls. This could reside in increased secretory demand placed on the beta cell by hyperglycemia or in the proinsulin conversion mechanism. In t his study, biosynthesis of the proinsulin conversion enzymes (PC2, PC3 , and carboxypeptidase-H [CP-H]) and proinsulin, were examined in isle ts isolated from 48-h infused rats with 50% (wt/vol) glucose (hypergly cemic, hyperinsulinemic, and increased pancreatic proinsulin to insuli n ratio), 20% (wt/vol) glucose (normoglycemic but hyperinsulinemic), a nd 0.45% (wt/vol) saline (controls). A decrease in the islet content o f PC2, PC3, and CP-H from hyperglycemic rats was observed. This reduct ion did not correlate with any deficiency in mRNA levels or biosynthes is of PC2, PC3, CP-H, or proinsulin. Furthermore, proinsulin conversio n rate was comparable in islets from hyperglycemic and control rats. H owever, in islets from hyperglycemic rats an abnormal increased propor tion of proinsulin was secreted, that was accompanied by an augmented release of PC2, PC3 and CP-H. Stimulation of the beta cell's secretory pathway by hyperglycemia, resulted in proinsulin being prematurely se creted from islets before its conversion could be completed. Thus, hyp erproinsulinemia induced by chronic hyperglycemia likely results from increased beta cell secretory demand, rather than a defect in the proi nsulin processing enzymes per se.