BETA-CELL LIPOTOXICITY IN THE PATHOGENESIS OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS OF OBESE RATS - IMPAIRMENT IN ADIPOCYTE-BETA-CELL RELATIONSHIPS

Hyperinsulinemia, loss of glucose-stimulated insulin secretion (GSIS), and peripheral insulin resistance coexist in non-insulin-dependent di abetes mellitus (NIDDM). Because free fatty acids (FFA) can induce the se same abnormalities, we studied their role in the pathogenesis of th e NIDDM of obese Zucker diabetic fatty (ZDP-drt) rats from 5 weeks of age (before the onset of hyperglycemia) until 14 weeks. Two weeks prio r to hyperglycemia, plasma FFA began to rise progressively, averaging 1.9 +/- 0.06 mM at the onset of hyperglycemia (P < 0.001 vs. controls) . At this time GSIS was absent and beta-cell GLUT-2 glucose transporte r was decreased. The triacylglycerol content of prediabetic islets ros e to 10 times that of controls and was correlated with plasma FFA (r = 0.825; P < 0.001), which, in turn, was correlated with the plasma glu cose concentration (r = 0.873; P < 0.001). Reduction of hyperlipacidem ia to 1.3 +/- 0.07 mM by pair feeding with lean littermates reduced al l beta-cell abnormalities and prevented hyperglycemia. Normal rat isle ts that had been cultured for 7 days in medium containing 2 mM FFA exh ibited increased basal insulin secretion at 3 mM glucose, and first-ph ase GSIS was reduced by 68 %; in prediabetic islets, first-phase GSIS was reduced by 69 % by FPA. The results suggest a role for hyperlipaci demia in the pathogenesis of NIDDM; resistance to insulin mediated ant ilipolysis is invoked to explain the high FFA despite hyperinsulinemia , and sensitivity of beta cells to hyperlipacedemia is invoked to expl ain the FFA-induced loss of GSIS.