Tumor Necrosis Factor α Produces Insulin Resistance in Skeletal Muscle by Activation of Inhibitor κB Kinase in a p38 MAPK-dependent Manner
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)-α caused insulin resistance on glucose uptake and GLUT4 translocation by impai...
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Published in | The Journal of biological chemistry Vol. 279; no. 17; p. 17070 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Biochemistry and Molecular Biology
23.04.2004
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Online Access | Get full text |
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Summary: | 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)-α 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-α 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-α.
However, in the presence of PD98059 or SP600125, inhibitors of p42/p44 MAPK or JNK, respectively, insulin resistance by TNF-α
was still produced. Moreover, TNF-α produced inhibitor κB kinase (IKK)-β activation and inhibitor κB-β and -α degradation
in a p38 MAPK-dependent manner, and treatment with salicylate (an inhibitor of IKK) completely restored insulin signaling.
Furthermore, TNF-α 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-α,
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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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M312021200 |