Endogenous nitric oxide inhibits glucose-induced insulin secretion by suppression of phosphofructokinase activity in pancreatic islets.

The physiological role of nitric oxide (NO) on the mechanism of insulin secretion is unknown, but some studies suggest that NO affects glucose metabolism in pancreatic beta-cells. We have aimed at clarifying the physiological role of endogenous NO and its target in the glucose metabolism of beta-cells. The expression of brain-type NO synthase (bNOS) was detected in pancreatic islets by Western blotting. Under the condition of elevated intracellular Ca2+ concentration induced in the beta-cells by high glucose and forced depolarization by 40 mM K+, the generation of NO from the islets was enhanced. This increase was suppressed by the NOS blockers, N-iminoethyl-l-ornithine (L-NIO), and exposure to Ca2+-free extracellular solution. In addition, the NOS blockers L-NIO and 7-nitro indazole (7-NI) enhanced glucose-induced but not glyceraldehyde- or KIC-induced insulin secretion. In an in vitro enzyme study, the NO donor sodium nitroprusside (SNP) suppressed phosphofructokinase activity and activated glucokinase and glucose-6-phosphate isomerase activity, but SNP significantly inhibited the combined activity of the enzymes. This suggests that endogenous NO has an inhibitory role on insulin release induced by glucose and that its underlying mechanism is the suppression of phosphofructokinase activity in glycolysis.