Nicotinamide inhibits IRF-1 mRNA induction and prevents IL-1 beta-induced nitric oxide synthase expression in pancreatic beta cells.
Nitric oxide produced by inducible nitric oxide synthase in islets exerts inhibitory and cytotoxic effects on pancreatic beta cells and is therefore thought to be a potent mediator in the pathogenesis of Type I diabetes mellitus. Here, using isolated rat pancreatic islets, we show that high-concentration nicotinamide (20 mM), but not low-concentration nicotinamide (5 mM), attenuates the interleukin-1 beta-evoked inhibition of glucose-induced insulin secretion by preventing the induction of interferon regulatory factor-1, a transcriptional factor which plays an essential role in inducible nitric oxide synthase gene expression, and the interleukin-1 beta-induced nitric oxide formation. High-concentration nicotinamide also restored an interleukin-1 beta-induced decrease in ATP content in pancreatic beta cells, suggesting that interleukin-1 beta-induced nitric oxide inhibits the mitochondrial function. The present results show the molecular basis of the preventive effect of high-dose nicotinamide on Type I diabetes mellitus.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D001549:Benzamides / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology; D050856:Interferon Regulatory Factor-1; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009536:Niacinamide / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D010750:Phosphoproteins / Q000096:biosynthesis*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis*; D019323:omega-N-Methylarginine
D001549:Benzamides; D017931:DNA Primers; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D007375:Interleukin-1; C494258:Irf1 protein, mouse; C494259:Irf1 protein, rat; D010750:Phosphoproteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014157:Transcription Factors; D009536:Niacinamide; D011064:Poly Adenosine Diphosphate Ribose; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C025160:3-aminobenzamide; D000255:Adenosine Triphosphate; D001120:Arginine; D019001:Nitric Oxide Synthase; D005947:Glucose