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 -cell failure and diabetes. Diazoxide (DZ 150 mg/kg. day), an inhibitor of insulin secretion, was administered to prediabetic ZDF animals for 8 weeks 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) ZL P < 0.01), whereas DZ-ZDF had higher insulin response to glucose than controls (P < 0.001). DZ improved HBA_1c (P < 0.001) and glucose tolearnce in ZDF (P < 0.001), but deteriorated HBA_1c in ZL rats (P < 0.02) despite normal tolerance in fasted state. DZ lowered plasma leptin (P < 0.001), free fatty acids and triglycerides (TG) (P < 0.001) levels, but increased adiponectin levels (P < 0.02) only in ZDF rats. DZ enhanced ₃-adrenorecptor (₃-AR) mRNA (P < 0.005) and adenylate cyclase (AC) activity (P < 0.01) in adipose tissue from ZDF rats only, whereas it enhanced islet (₃AR) mRNA (P < 0.005) but paradoxically decreased islets AC activity (P < 0.005) in these animals. Islet fatty acid synthase mRNA (P < 0.03), acyl CoA carboxylase mRNA (P < 0.01), uncoupling protein-2 mRNA (P < 0.01) and TG contents (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). Diazoxide-induced -cell rest improved lipid profile, enhanced metabolic efficiency of insulin prevented -cell dysfunction and diabetes in diabetes-prone animals. This therapeutic strategy may be beneficial in preventing -cell failure and progression to diabetes in humans.