Basal insulin hypersecretion in insulin-resistant Zucker diabetic and Zucker fatty rats: Role of enhanced fuel metabolism

The biochemical mechanisms responsible for basal hyperinsulinemia in insuli n-resistant states have not been fully defined. We therefore studied pancre atic beta-cell function in vitro to characterize the relative importance of fuel metabolism or secretion via a constitutive pathway in the maintenance of high basal insulin secretion in Zucker diabetic fatty (ZDF) and Zucker fatty (ZF) rats. Insulin secretion from ZF (10 +/- 1.8 v 5 +/- 0.6 pmol/ng DNA/h) and ZDF (30 +/- 4 v 7 +/- 0.8 pmol/ng DNA/h) islets at 2.8 mmol/L gl ucose was two to four times greater than secretion from islets of lean litt ermate control rats. In response to a decreasing glucose concentration (fro m 12 to 0 mmol/L), a paradoxical increase in insulin secretion was observed in perfused ZDF rat pancreas. Insulin secretion at 2.8 mmol/L glucose was suppressed approximately 70% to 80% in islets from ZDF and ZF rats followin g exposure to diazoxide, a K+-adenosine triphosphate (K-ATP) channel opener that inhibits membrane depolarization, or rotenone and oligomycin, agents that inhibit AIP production, or by incubation at 23 degrees C. Inhibition o f glycolysis with mannoheptulose, 2-deoxyglucose, and iodoacetate or fatty acid oxidation with a carnitine palmitoyltransferase I inhibitor also signi ficantly inhibited basal insulin secretion in islets of ZDF and ZF rats but not their lean littermates. Furthermore, the glycolytic flux at 2.8 mmol/L glucose was significantly higher in ZDF islets versus ZDF lean littermate (ZLC) islets (2.2 +/- 0.1 v 3.7 +/- 0.3 pmol/ng DNA/2 h, P <.01) and was su ppressed by mannoheptulose. In ZDF and ZF islets, high basal insulin secret ion was maintained despite a 50% reduction in the rate of proinsulin/insuli n biosynthesis at 2.8 mmol/L glucose. The rate of proinsulin to insulin con version and the ratio of proinsulin to insulin secretion by islets of ZDF r ats were similar to the values in the lean littermates. Thus, basal hyperse cretion in these two insulin-resistant models appears to be related to enha nced fuel metabolism rather than the contribution of a constitutive pathway of secretion. Copyright (C) 1999 by W.B. Saunders Company.