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.
Sjöholm
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Department of Molecular Medicine, Rolf Luft Center for Diabetes Research, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
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