Signal transduction in islet hormone release: interaction of nitric oxide with basal and nutrient-induced hormone responses

We examined the relation between the islet NO system and islet hormone secretion induced by either the non-glucose nutrient alpha-ketoisocaproic acid (KIC) or, in some experiments, glucose. KIC dose dependently stimulated Insulin but inhibited glucagon secretion. In a medium devoid of any nutrient, the NO Synthase (NOS)-inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) induced an increase in basal Insulin release but a decrease in glucagon release. These effects were evident also in K+-depolarised islets. KIC-induced Insulin release was increased by L-NAME. This increase was abolished in K+-depolarised islets. In contrast, glucose- induced Insulin release was potentiated by L-NAME after K+ depolarisation. The intracellular NO donor hydroxylamine dose dependently inhibited KIC-stimulated Insulin release and reversed KIC-induced suppression of glucagon release. Our data suggest that islet hormone secretion in a medium devoid of nutrients is greatly affected by the islet NO system, whereas KIC-induced secretion is little affected. Glucose-induced Insulin release, however, is accompanied by increased NOS activity, the NOS-activating signal being derived from the glycolytic-pentose shunt part of glucose metabolism. The observed NO effects on islet hormone release can proceed independently of membrane-depolarisation events.