NICOTINAMIDE INHIBITS IRF-1 MESSENGER-RNA 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 exe rts inhibitory and cytotoxic effects on pancreatic beta cells and is t herefore thought to be a potent mediator in the pathogenesis of Type I diabetes mellitus. Here, using isolated rat pancreatic islets, we sho w that high-concentration nicotinamide (20 mM), but not low-concentrat ion nicotinamide (5 mM) attenuates the interleukin-1 beta-evoked inhib ition of glucose-induced insulin secretion by preventing the induction of interferon regulatory factor-1, a transcriptional factor which pla ys an essential role in inducible nitric oxide synthase gene expressio n, and the interleukin-1 beta-induced nitric oxide formation. High-con centration nicotinamide also restored an interleukin-1 beta-induced de crease in ATP content in pancreatic beta cells, suggesting that interl eukin-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. (C) 1995 Acade mic Press, Inc.