NITRIC-OXIDE DONOR SIN-1 INHIBITS INSULIN RELEASE

Preceding the onset of insulin-dependent diabetes mellitus, pancreatic islets are infiltrated by macrophages secreting interleukin-1 beta, w hich exerts cytotoxic and inhibitory actions on islet beta-cell insuli n secretion through induction of nitric oxide (NO) synthesis. The infl uence of the NO donor 3-morpholinosydnonimine (SIN-1) on insulin secre tion from isolated pancreatic islets in response to various secretagog ues was investigated. Stimulation of insulin release evoked by glucose , phospholipase C activation with carbachol, and protein kinase C acti vation with phorbol ester were obtunded by SIN-1, whereas the response to adenylyl cyclase activation or K+-induced depolarization was not a ffected. It is concluded that enzymes involved in glucose catabolism, phospholipase C or protein kinase C, may be targeted by NO. Reversal o f SIN-1 inhibition of glucose-stimulated insulin release by dithiothre itol suggests that NO may inhibit insulin secretion partly by S-nitros ylation of thiol residues in key proteins in the stimulus-secretion co upling. These adverse effects of NO on the p-cell stimulus-secretion c oupling may be of importance for the development of the impaired insul in secretion characterizing diabetes mellitus.