Abstract

Insulin resistance is a common problem associated with infections and cancer and, most importantly, is the central component of non-insulin-dependent diabetes mellitus. We have recently shown that tumor necrosis factor (TNF) alpha is a key mediator of insulin resistance in animal models of non-insulin-dependent diabetes mellitus. Here, we investigate how TNF-alpha interferes with insulin action. Chronic exposure of adipocytes to low concentrations of TNF-alpha strongly inhibits insulin-stimulated glucose uptake. Concurrently, TNF-alpha treatment causes a moderate decrease in the insulin-stimulated autophosphorylation of the insulin receptor (IR) and a dramatic decrease in the phosphorylation of IR substrate 1, the major substrate of the IR in vivo. The IR isolated from TNF-alpha-treated cells is also defective in the ability to autophosphorylate and phosphorylate IR substrate 1 in vitro. These results show that TNF-alpha directly interferes with the signaling of insulin through its receptor and consequently blocks biological actions of insulin.

Keywords

Insulin receptorInsulin resistanceAutophosphorylationInsulinInternal medicineEndocrinologyInsulin receptor substrateIRS1Tumor necrosis factor alphaDiabetes mellitusIRS2BiologyPhosphorylationChemistryMedicineCell biologyProtein kinase A

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Publication Info

Year
1994
Type
article
Volume
91
Issue
11
Pages
4854-4858
Citations
1189
Access
Closed

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Gökhan S. Hotamışlıgil, David Murray, Lisa Choy et al. (1994). Tumor necrosis factor alpha inhibits signaling from the insulin receptor.. Proceedings of the National Academy of Sciences , 91 (11) , 4854-4858. https://doi.org/10.1073/pnas.91.11.4854

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DOI
10.1073/pnas.91.11.4854