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J Biol Chem, Vol. 274, Issue 26, 18702-18708, June 25, 1999

Tumor Necrosis Factor -induced Pancreatic -Cell Insulin Resistance Is Mediated by Nitric Oxide and Prevented by 15-Deoxy-^12,14-prostaglandin J₂ and Aminoguanidine
A ROLE FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR  ACTIVATION AND iNOS EXPRESSION

From the Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

Recent studies have identified a -cell insulin receptor that functions in the regulation of protein translation and mitogenic signaling similar to that described for insulin-sensitive cells. These findings have raised the novel possibility that -cells may exhibit insulin resistance similar to skeletal muscle, liver, and fat. To test this hypothesis, the effects of tumor necrosis factor- (TNF), a cytokine proposed to mediate insulin resistance by interfering with insulin signaling at the level of the insulin receptor and its substrates, was evaluated. TNF inhibited p70^s6k activation by glucose-stimulated -cells of the islets of Langerhans in a dose- and time-dependent manner, with maximal inhibition observed at ~20-50 ng/ml, detected after 24 and 48 h of exposure. Exogenous insulin failed to prevent TNF-induced inhibition of p70^s6k_, suggesting a defect in the insulin signaling pathway. To further define mechanisms responsible for this inhibition and also to exclude cytokine-induced nitric oxide (NO) as a mediator, the ability of exogenous or endogenous insulin ± inhibitors of nitric-oxide synthase (NOS) activity, aminoguanidine or N-monomethyl-L-arginine, was evaluated. Unexpectedly, TNF and also interleukin 1 (IL-1)-induced inhibition of p70^s6k was completely prevented by inhibitors that block NO production. Western blot analysis verified inducible NOS (iNOS) expression after TNF exposure. Furthermore, the ability of IL-1 receptor antagonist protein, IRAP, to block TNF-induced inhibition of p70^s6k indicated that activation of intra-islet macrophages and the release of IL-1 that induces iNOS expression in -cells was responsible for the inhibitory effects of TNF. This mechanism was confirmed by the ability of the peroxisome proliferator-activated receptor- agonist 15-deoxy-^12,14-prostaglandin J₂ to attenuate TNF-induced insulin resistance by down-regulating iNOS expression and/or blocking IL-1 release from activated macrophages. Overall, TNF-mediated insulin resistance in -cells is characterized by a global inhibition of metabolism mediated by NO differing from that proposed for this proinflammatory cytokine in insulin-sensitive cells.

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