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      Tumor necrosis factor alpha produces insulin resistance in skeletal muscle by activation of inhibitor kappaB kinase in a p38 MAPK-dependent manner.

      The Journal of Biological Chemistry

      Animals, Biological Transport, Blotting, Western, Cell Membrane, metabolism, Cells, Cultured, Enzyme Activation, Enzyme Inhibitors, pharmacology, Glucose, pharmacokinetics, I-kappa B Kinase, Insulin, Insulin Receptor Substrate Proteins, Insulin Resistance, Intracellular Signaling Peptides and Proteins, Mitogen-Activated Protein Kinases, Muscle, Skeletal, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Precipitin Tests, Protein Transport, Protein-Serine-Threonine Kinases, Rats, Salicylic Acid, Serine, Signal Transduction, Subcellular Fractions, Time Factors, Tumor Necrosis Factor-alpha, physiology, Tyrosine, chemistry, p38 Mitogen-Activated Protein Kinases

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          Insulin stimulation produced a reliable 3-fold increase in glucose uptake in primary neonatal rat myotubes, which was accompanied by a similar effect on GLUT4 translocation to plasma membrane. Tumor necrosis factor (TNF)-alpha caused insulin resistance on glucose uptake and GLUT4 translocation by impairing insulin stimulation of insulin receptor (IR) and IR substrate (IRS)-1 and IRS-2 tyrosine phosphorylation, IRS-associated phosphatidylinositol 3-kinase activation, and Akt phosphorylation. Because this cytokine produced sustained activation of stress and proinflammatory kinases, we have explored the hypothesis that insulin resistance by TNF-alpha could be mediated by these pathways. In this study we demonstrate that pretreatment with PD169316 or SB203580, inhibitors of p38 MAPK, restored insulin signaling and normalized insulin-induced glucose uptake in the presence of TNF-alpha. However, in the presence of PD98059 or SP600125, inhibitors of p42/p44 MAPK or JNK, respectively, insulin resistance by TNF-alpha was still produced. Moreover, TNF-alpha produced inhibitor kappaB kinase (IKK)-beta activation and inhibitor kappaB-beta and -alpha degradation in a p38 MAPK-dependent manner, and treatment with salicylate (an inhibitor of IKK) completely restored insulin signaling. Furthermore, TNF-alpha produced serine phosphorylation of IR and IRS-1 (total and on Ser(307) residue), and these effects were completely precluded by pretreatment with either PD169316 or salicylate. Consequently, TNF-alpha, through activation of p38 MAPK and IKK, produces serine phosphorylation of IR and IRS-1, impairing its tyrosine phosphorylation by insulin and the corresponding activation of phosphatidylinositol 3-kinase and Akt, leading to insulin resistance on glucose uptake and GLUT4 translocation.

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