Inosine-stimulated insulin release and metabolism of inosine in isolated mouse pancreatic islets

Abstract

Inosine is a potent primary stimulus of insulin secretion from isolated mouse islets. The inosine-induced insulin secretion was totally depressed during starvation, but was completely restored by the addition of 5 mM-caffeine to the medium and partially restored by the addition of 5mM-glucose. Mannoheptulose (3 mg/ml) potentiated the effect of 10mM-inosine in islets from fed mice. The mechanism of the stimulatory effect of inosine was further investigated, and pancreatic islets contain a nucleoside phosphorylase capable of converting inosine into hypoxanthine and ribose 1-phosphate. Inosine at 10 mM concentration increased the lactate production and the content of ATP, G-6-P (fructose 1,6-diphosphate + triose phosphates) and cyclic AMP [cAMP] in islets from fed mice. In islets from starved mice inosine-induced lactate production was decreased and no change in the concentration of cAMP could be demonstrated, whereas the concentration of ATP and G-6-P rose. Inosine (10 mM) induced a higher concentration of (fructose 1,6-diphosphate + triose phosphates) in islets from starved mice than in islets from fed mice suggesting that in starvation the activities of glyceraldehyde 3-phosphate dehydrogenase or other enzymes below this step in glycolysis are decreased. Formation of glucose from inosine was negligible. Inosine had no direct effect on adenylate cyclase activity in islet homogenates. The observed changes in insulin secretion and islet metabolism mimic what is seen when glucose and glyceraldehyde stimulate insulin secretion, and as neither ribose nor hypoxanthine-stimulated insulin release, the results are interpreted as supporting the substratesite hypothesis for glucose-induced insulin secretion according to which glucose has to be metabolized in the .beta.-cells before secretion is initiated.