CHRONIC EXPOSURE TO FREE FATTY-ACID REDUCES PANCREATIC BETA-CELL INSULIN CONTENT BY INCREASING BASAL INSULIN-SECRETION THAT IS NOT COMPENSATED FOR BY A CORRESPONDING INCREASE IN PROINSULIN BIOSYNTHESIS TRANSLATION

The pancreatic beta cell normally maintains a stable balance among ins ulin secretion, insulin production, and insulin degradation to keep op timal intracellular stores of the hormone, Elevated levels of FFA mark edly enhance insulin secretion; however, the effects of FFA on insulin production and intracellular stores remain unclear, In this study, tw ofold elevation in total circulating FFA effected by infusion of lard oil and heparin into rats for 6 fa under normoglycemic conditions resu lted in a marked elevation of circulating insulin levels evident after 4 h, and a 30% decrease in pancreatic insulin content after a 6-h inf usion in vivo, Adding 125 mu M oleate to isolated rat pancreatic islet s cultured with 5.6 mM glucose caused a 50% fall in their insulin cont ent over 24 h, coupled with a marked enhancement of basal insulin secr etion, Both effects of fatty acid were blocked by somatostatin, In con trast to the stimulatory effects of oleate on insulin secretion, gluco se-induced proinsulin biosynthesis was inhibited by oleate up to 24 h, hut was unaffected thereafter, This result was ire spite of a two-to threefold oleate-induced increase in preproinsulin mRNA levels, unders coring the importance of translational regulation of proinsulin biosyn thesis in maintaining beta cell insulin stores, Collectively, these re sults suggest that chronically elevated FFA contribute to beta cell dy sfunction in the pathogenesis of NIDDM by significantly increasing the basal rate of insulin secretion, This increase in turn results ira a decrease in the beta cell's intracellular stores that cannot be offset by commensurate FFA induction of proinsulin biosynthesis.