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)
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)
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DOI：
10.2337/diabetes.54.4.959
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发表时间：
2005-04-01
期刊：
影响因子：
7.7
通讯作者：
Saad, MJA
中科院分区：
文献类型：
--
作者：
Carvalho, MA;Ueno, M;Saad, MJA
有证据表明，外源性一氧化氮（NO）和诱导型一氧化氮合酶（iNOS）产生的NO可诱导肌肉胰岛素抵抗。在这里，我们研究了这种胰岛素抵抗是否可以介导的S-亚硝基化的蛋白质参与胰岛素信号转导途径的早期步骤。由S-亚硝基谷胱甘肽（GSNO）提供的外源性NO在体外和体内诱导胰岛素受体β亚单位（IR β）和蛋白激酶B/Alkt（Akt）的S-亚硝基化，并降低其在肌肉中的激酶活性。胰岛素受体底物（IRS）-1也迅速S-亚硝化，其表达减少慢性GSNO治疗后。在两种不同的模型中，胰岛素抵抗与iNOS表达增强相关-饮食诱导的肥胖和肥胖/肥胖糖尿病小鼠-我们观察到肌肉中IR β/IRS-1和Akt的S-亚硝基化增强。通过减少iNOS表达来抑制这些蛋白质的S-亚硝化，在两种动物模型中均产生了胰岛素作用的改善。因此，参与胰岛素信号转导的蛋白质的S-亚硝基化是iNOS诱导胰岛素抵抗的新分子机制。
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.