S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt - A novel mechanism of insulin resistance (Publication with Expression of Concern)

被引:215
作者
Carvalho, MA
Ueno, M
Hirabara, SM
Seabra, AB
Carvalheira, JBC
de Oliveira, MG
Velloso, LA
Curi, R
Saad, MJA
机构
[1] Univ Estadual Campinas, Dept Internal Med, BR-13081970 Campinas, SP, Brazil
[2] Univ Sao Paulo, Dept Physiol & Biophys, Sao Paulo, Brazil
[3] Univ Estadual Campinas, Inst Chem, BR-13081970 Campinas, SP, Brazil
基金
巴西圣保罗研究基金会;
关键词
D O I
10.2337/diabetes.54.4.959
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 beta subunit (IR beta) and protein kinase B/Alkt (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 IR beta/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.
引用
收藏
页码:959 / 967
页数:9
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