Tumor necrosis factor alpha-induced pancreatic beta-cell insulin resistance is mediated by nitric oxide and prevented by 15-deoxy-Delta12,14-prostaglandin J2 and aminoguanidine. A role for peroxisome proliferator-activated receptor gamma 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 (TNFalpha), a cytokine proposed to mediate insulin resistance by interfering with insulin signaling at the level of the insulin receptor and its substrates, was evaluated. TNFalpha 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 approximately 20-50 ng/ml, detected after 24 and 48 h of exposure. Exogenous insulin failed to prevent TNFalpha-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, TNFalpha 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 TNFalpha exposure. Furthermore, the ability of IL-1 receptor antagonist protein, IRAP, to block TNFalpha-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 TNFalpha. This mechanism was confirmed by the ability of the peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-Delta12, 14-prostaglandin J2 to attenuate TNFalpha-induced insulin resistance by down-regulating iNOS expression and/or blocking IL-1 release from activated macrophages. Overall, TNFalpha-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.
Kwon
G
G
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Xu
G
G
Marshall
C A
CA
McDaniel
M L
ML
D000818:Animals; D002839:Chromans / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000187:drug effects*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism*; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002839:Chromans; D006146:Guanidines; D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019893:Ribosomal Protein S6 Kinases; D000077288:Troglitazone; D015230:Prostaglandin D2; C004479:pimagedine