Diazoxide Causes Recovery of β-Cell Glucose Responsiveness in 90% Pancreatectomized Diabetic Rats

Chronic hyperglycemia causes near-total disappearance of glucose-induced insulin secretion. The etiology has been suggested to be a nonsustainable stimulation of insulin release that causes β-cells to become unresponsive to glucose through an undefined mechanism. We used an inhibitor 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 day 8, 15, or 22. In vitro pancreas perfusions were conducted 36 h posttreatment (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 arginine. In 2-week Px rats, insulin responses to 16.7 mM glucose and to glucose/arginine were both appropriate for the reduced β-cell mass, i.e., no defect in β-cell glucose responsiveness had yet occurred. Diazoxide had no affect on insulin release at this time. Between 2 and 3 weeks after pancreatectomy, insulin output to 16.7 mM glucose fell 75%, and that to glucose/arginine fell 50%. Diazoxide given at this time partially blocked the fall in glucose-induced insulin secretion and totally prevented that with arginine. The increased insulin secretion caused by diazoxide was accompanied by 1 ) lower nonfasting plasma glucose values, 2 ) improved glucose tolerance after oral glucose load, and 3 ) a 50% increase in pancreatic insulin content. Our results support the concept that excessive insulin secretion is a major cause of the hyperglycemia-induced loss of β-cell glucose responsiveness. A leading candidate for the mechanism of this effect is depleted pancreatic insulin stores. Overstimulation of insulin secretion provides a new target for pharmacological therapy aimed at reducing glucose intolerance in non-insulin-dependent diabetes mellitus.