HYPERPROINSULINEMIA IN THE DIABETIC PSAMMOMYS-OBESUS IS A RESULT OF INCREASED SECRETORY DEMAND ON THE BETA-CELL

We have recently shown that the diabetic syndrome in Psammomys obesus is characterized by severe depletion of islet immunoreactive insulin ( IRI) stores together with a marked increase in the islet proinsulin to insulin ratio. In the present in vitro studies, we show marked enhanc ement of proinsulin biosynthesis in islets from diabetic P. obesus (si milar to 8-fold compared to nondiabetic islets). Proinsulin to insulin conversion and insulin degradation do not differ significantly betwee n diabetic and nondiabetic islets. The rate of IRI secretion at a stim ulatory concentration of glucose (16.7 mM) is comparable in diabetic a nd nondiabetic animals, but at a nonstimulatory glucose concentration (0 man), islets obtained from diabetic animals show significant IRI re lease. beta-Cells from diabetic P. obesus also exhibited increased sec retion of newly synthesized proinsulin and conversion intermediates un der stimulatory conditions. Moreover, a novel secretory compartment, h ighly enriched in newly synthesized C peptide, characterized the beta- cells of diabetic animals. Our data suggest that the marked insulin de pletion observed in diabetic islets is probably due to a hyperglycemia -driven increase ill secretory demand that is not met by the enhanced biosynthetic capacity of these islets. This leads to relative enrichme nt of the depleted diabetic islets with immature secretory granules of a higher proinsulin content.