DIAZOXIDE CAUSES RECOVERY OF BETA-CELL GLUCOSE RESPONSIVENESS IN 90-PERCENT PANCREATECTOMIZED DIABETIC RATS

Chronic hyperglycemia causes near-total disappearance of glucose-induc ed insulin secretion. The etiology has been suggested to be a nonsusta inable stimulation of insulin release that causes beta-cells to become unresponsive to glucose through an undefined mechanism. We used an in hibitor of insulin secretion, diazoxide, to test this hypothesis in 90 % pancreatectomized (Px) rats. Px rats were given 5 days of diazoxide (30 mg/kg orally twice a day) or tap water starting on postoperative d ay 8, 15, or 22. In vitro pancreas perfusions were conducted 36 h post treatment (2, 3, or 4 weeks after surgery) using a protocol of 15 min of 16.7 mM glucose followed by 15 min of 16.7 mM glucose plus 10 mM ar ginine. In 2-week Px rats, insulin responses to 16.7 mM glucose and to glucose/arginine were both appropriate for the reduced beta-cell mass , i.e., no defect in beta-cell glucose responsiveness had yet occurred . Diazoxide had no affect on insulin release at this time. Between 2 a nd 3 weeks after pancreatectomy, insulin output to 16.7 mM glucose fel l 75%, and that to glucose/arginine fell 50%. Diazoxide given at this time partially blocked the fall in glucose-induced insulin secretion a nd totally prevented that with arginine. The increased insulin secreti on caused by diazoxide was accompanied by 1) lower nonfasting plasma g lucose values, 2) improved glucose tolerance after oral glucose load, and 3) a 50% increase in pancreatic insulin content. Our results suppo rt the concept that excessive insulin secretion is a major cause of th e hyperglycemia-induced loss of beta-cell glucose responsiveness. A le ading candidate for the mechanism of this effect is depleted pancreati c insulin stores. Overstimulation of insulin secretion provides a new target for pharmacological therapy aimed at reducing glucose intoleran ce in non-insulin-dependent diabetes mellitus.