Abstract

Tumor necrosis factor-α (TNF-α) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor (IR). Treatment of cultured murine adipocytes with TNF-α was shown to induce serine phosphorylation of insulin receptor substrate 1 (IRS-1) and convert IRS-1 into an inhibitor of the IR tyrosine kinase activity in vitro. Myeloid 32D cells, which lack endogenous IRS-1, were resistant to TNF-α-mediated inhibition of IR signaling, whereas transfected 32D cells that express IRS-1 were very sensitive to this effect of TNF-α. An inhibitory form of IRS-1 was observed in muscle and fat tissues from obese rats. These results indicate that TNF-α induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling.

Keywords

Insulin resistanceInsulin receptorInternal medicineEndocrinologyInsulin receptor substrateTyrosine kinaseIRS2InsulinIRS1Tumor necrosis factor alphaChemistryBiologyReceptorMedicine

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Publication Info

Year
1996
Type
article
Volume
271
Issue
5249
Pages
665-670
Citations
2570
Access
Closed

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Gökhan S. Hotamışlıgil, Pascal Peraldi, Adriane I. Budavari et al. (1996). IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin Resistance. Science , 271 (5249) , 665-670. https://doi.org/10.1126/science.271.5249.665

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DOI
10.1126/science.271.5249.665