Glucagon decreases cytokine induction of nitric oxide synthase and action on insulin secretion in RIN5F cells and rat and human islets of Langerhans

Nitric oxide synthase, induced by cytokines in insulin-containing cells, pr oduces nitric oxide which inhibits function and may promote cell killing. S ince glucagon was shown to prevent inducible nitric oxide synthase (iNOS) e xpression in rat hepatocytes it was of interest to examine the action of gl ucagon (and cyclic AMP) on iNOS induction in insulin-producing cells, Cultu red RIN5F cells and primary rat and human islets of Langerhans were treated with interleukin 1 beta (IL-1 beta) or a combination of cytokines, and wer e co-treated or pre-treated with glucagon, In RIN5F cells, the activity of iNOS induced by IL-1 beta (10 pM, 24 h), was significantly reduced by gluca gon (1000 nM), which raises cyclic AMP, and by forskolin (1-10 mu M), a non specific activator of adenylate cyclase, Glucagon and forskolin also decre ased iNOS expression in RIN5F cells, and rat and human islets, as shown by Western blotting. The inhibitory action of IL-1 beta (100 pM, 24 h) on rat islet insulin secretion was partially reversed by 1-h pre-treatment with gl ucagon (10-1000 nM), while the contrasting stimulatory effect of 48-h treat ment with cytokines on insulin secretion from human islets was similarly pr evented by glucagon (1000 nM) pre-treatment. These results suggest that glu cagon inhibits iNOS expression in insulin-containing cells and imply that g lucagon could modulate the inhibitory effects of cytokines. (C) 1999 Academ ic Press.