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Diabetes 54:959-967, 2005
© 2005 by the American Diabetes Association, Inc.

S-Nitrosation of the Insulin Receptor, Insulin Receptor Substrate 1, and Protein Kinase B/Akt

A Novel Mechanism of Insulin Resistance

Marco A. Carvalho-Filho1, Mirian Ueno1, Sandro M. Hirabara2, Amedea B. Seabra3, José B.C. Carvalheira1, Marcelo G. de Oliveira3, Lício A. Velloso1, Rui Curi2, and Mario J.A. Saad1

1 Department of Internal Medicine, State University of Campinas, UNICAMP, Campinas, Brazil
2 Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil
3 Chemistry Institute, State University of Campinas, UNICAMP, Campinas, Brazil

Evidence demonstrates that exogenous nitric oxide (NO) and the NO produced by inducible nitric oxide synthase (iNOS) can induce insulin resistance in muscle. Here, we investigated whether this insulin resistance could be mediated by S-nitrosation of proteins involved in early steps of the insulin signal transduction pathway. Exogenous NO donated by S-nitrosoglutathione (GSNO) induced in vitro and in vivo S-nitrosation of the insulin receptor ß subunit (IRß) and protein kinase B/Akt (Akt) and reduced their kinase activity in muscle. Insulin receptor substrate (IRS)-1 was also rapidly S-nitrosated, and its expression was reduced after chronic GSNO treatment. In two distinct models of insulin resistance associated with enhanced iNOS expression—diet-induced obesity and the ob/ob diabetic mice—we observed enhanced S-nitrosation of IRß/IRS-1 and Akt in muscle. Reversal of S-nitrosation of these proteins by reducing iNOS expression yielded an improvement in insulin action in both animal models. Thus, S-nitrosation of proteins involved in insulin signal transduction is a novel molecular mechanism of iNOS-induced insulin resistance.

Address correspondence and reprint requests to Mario J.A. Saad, Departamento de Clínica Médica, FCM, UNICAMP, 13081 970, Campinas, Brazil. Email: msaad{at}fcm.unicamp.br


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