Modulation of adipoinsular axis in prediabetic Zucker diabetic fatty rats by diazoxide

Dysregulation of the adipoinsular axis in male obese Zucker diabetic fatty (ZDF; fa/fa) rats, a model of type 2 diabetes, results in chronic hyperinsulinemia and increased de novo lipogenesis in islets, leading to beta-cell failure and diabetes. Diazoxide (DZ; 150 mg/kg.d), an inhibitor of insulin secretion, was administered to prediabetic ZDF animals for 8 wk as a strategy for prevention of diabetes. DZ reduced food intake (P<0.02) and rate of weight gain only in ZDF rats (P<0.01). Plasma insulin response to glucose load was attenuated in DZ-Zucker lean rats (ZL; P<0.01), whereas DZ-ZDF had higher insulin response to glucose than controls (P<0.001). DZ improved hemoglobin A(1c) (P<0.001) and glucose tolerance in ZDF (P<0.001), but deteriorated hemoglobin A(1c) in ZL rats (P<0.02) despite normal tolerance in the fasted state. DZ lowered plasma leptin (P<0.001), free fatty acid, and triglyceride (P<0.001) levels, but increased adiponectin levels (P<0.02) only in ZDF rats. DZ enhanced beta(3)-adrenoreceptor mRNA (P<0.005) and adenylate cyclase activity (P<0.01) in adipose tissue from ZDF rats only, whereas it enhanced islet beta(3)-adrenergic receptor mRNA (P<0.005) but paradoxically decreased islet adenylate cyclase activity (P<0.005) in these animals. Islet fatty acid synthase mRNA (P<0.03), acyl coenzyme A carboxylase mRNA (P<0.01), uncoupling protein-2 mRNA (P<0.01), and triglyceride content (P<0.005) were only decreased in DZ-ZDF rats, whereas islet insulin mRNA and insulin content were increased in DZ-ZDF (P<0.01) and DZ-ZL rats (P<0.03). DZ-induced beta-cell rest improved the lipid profile, enhanced the metabolic efficiency of insulin, and prevented beta-cell dysfunction and diabetes in diabetes-prone animals. This therapeutic strategy may be beneficial in preventing beta-cell failure and progression to diabetes in humans.