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

A Novel Mechanism of Insulin Resistance

  1. Marco A. Carvalho-Filho1,
  2. Mirian Ueno1,
  3. Sandro M. Hirabara2,
  4. Amedea B. Seabra3,
  5. José B.C. Carvalheira1,
  6. Marcelo G. de Oliveira3,
  7. Lício A. Velloso1,
  8. Rui Curi2 and
  9. Mario J.A. Saad1
  1. 1Department of Internal Medicine, State University of Campinas, UNICAMP, Campinas, Brazil
  2. 2Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil
  3. 3Chemistry Institute, State University of Campinas, UNICAMP, Campinas, Brazil
  1. 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

Abstract

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 β subunit (IRβ) 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 IRβ/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.

Footnotes

    • Accepted January 1, 2005.
    • Received June 10, 2004.
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