Studies of Insulin Secretion in the Perfused Rat Pancreas: Effect of Diazoxide and A025

Abstract

Continuous glucose stimulation produces two phases of insulin secretion in the isolated perfused rat pancreas. Puromycin has no effect on the first phase but partially inhibits the second. The second phase has been reported previously to be associated in part with insulin synthesis. In acute experiments, diazoxide and its derivative—A025—inhibit insulin secretion in both phases. This inhibition corresponds with an increase of the pancreatic tissue insulin content. These results suggest that both A025 and diazoxide decrease insulin release but have no effect on its synthesis. In pancreatic perfusion of rats which had been chronically treated with diazoxide and A025 (per os), and who had been fasted and without drug for sixteen hours before the experiment, a greater insulin secretion was demonstrated in both phases compared with normal controls; however, if the perfusion is done three to four hours after the last dose, the amount of insulin secreted is smaller than the respective controls. This again suggests that during the period of action of the drug, pancreatic insulin is not released, but synthesis is not inhibited. The result, therefore, is an accumulation of insulin within the beta cells. The acute and chronic experiments done under our experimental conditions in the perfused rat pancreas suggest that diazoxide and A025 inhibit insulin release, but have no effect on insulinogenesis.