Tumor necrosis factor α-induced pancreatic β-cell insulin resistance is mediated by nitric oxide and prevented by 15-deoxy-Δ12,14-prostaglandin J2 and aminoguanidine -: A role for peroxisome proliferator-activated receptor γ activation and iNOS expression

Recent studies have identified a beta-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 beta-cells may exhibit insulin resistance similar to skeletal muscle, liver, and fat. To test this hypothesis, the effects of tumor necrosis factor-alpha (TNF alpha), 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 alpha inhibited p70(s6k) activation by glucose-stimulated beta-cells of the islets of Langerhans in a dose- and time-dependent manner, with maximal inhibition observed at similar to 20-50 ng/ml, detected after 24 and 48 h of exposure. Exogenous insulin failed to prevent TNF alpha-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, TNFa 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 (MOS) expression after TNF alpha exposure. Furthermore, the ability of IL-1 receptor antagonist protein, IRAP, to block TNF alpha-induced inhibition of p70(s6k) indicated that activation of intra-islet macrophages and the release of IL-1 that induces iNOS expression in beta-cells was responsible for the inhibitory effects of TNF alpha. This mechanism was confirmed by the ability of the peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) to attenuate TNF alpha-induced insulin resistance by down-regulating MOS expression and/or blocking IL-1 release from activated macrophages. Overall, TNF alpha-mediated insulin resistance in beta-cells is characterized by a global inhibition of metabolism mediated by NO differing from that proposed for this proinflammatory cytokine in insulin-sensitive cells.