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, which exerts cytotoxic and inhibitory actions on islet beta-cell insulin secretion through induction of nitric oxide (NO) synthesis. The influence of the NO donor 3-morpholinosydnonimine (SIN-1) on insulin secretion from isolated pancreatic islets in response to various secretagogues was investigated. Stimulation of insulin release evoked by glucose, phospholipase C activation with carbachol, and protein kinase C activation with phorbol ester were obtained by SIN-1, whereas the response to adenylyl cyclase activation or K(+)-induced depolarization was not affected. It is concluded that enzymes involved in glucose catabolism, phospholipase C or protein kinase C, may be targeted by NO. Reversal of SIN-1 inhibition of glucose-stimulated insulin release by dithiothreitol suggests that NO may inhibit insulin secretion partly by S-nitrosylation of thiol residues in key proteins in the stimulus-secretion coupling. These adverse effects of NO on the beta-cell stimulus-secretion coupling may be of importance for the development of the impaired insulin secretion characterizing diabetes mellitus.
Department of Molecular Medicine, Rolf Luft Center for Diabetes Research, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
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Sjöholm
D017607:Aluminum Compounds / Q000494:pharmacology; D000818:Animals; D000252:Calcium-Transporting ATPases / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D004229:Dithiothreitol / Q000494:pharmacology; D005459:Fluorides / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D010084:Oxidation-Reduction; D011189:Potassium Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012636:Secretory Rate / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D017607:Aluminum Compounds; D007328:Insulin; D005576:Colforsin; D009569:Nitric Oxide; C002385:linsidomine; D011189:Potassium Chloride; D002217:Carbachol; D008981:Molsidomine; D000242:Cyclic AMP; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D000252:Calcium-Transporting ATPases; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate; D005459:Fluorides; D004229:Dithiothreitol; C032311:aluminum fluoride