S-Nitrosation of the Insulin Receptor, Insulin Receptor Substrate 1, and Protein Kinase B/Akt: A Novel Mechanism of Insulin Resistance (original) (raw)
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S-Nitrosation of the Insulin Receptor, Insulin Receptor Substrate 1, and Protein Kinase B/Akt
Diabetes, 2005
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 mo...
Nitric oxide agents impair insulin-mediated signal transduction in rat skeletal muscle
BMC biochemistry, 2006
Evidence demonstrates that exogenously administered nitric oxide (NO) can induce insulin resistance in skeletal muscle. We have investigated the modulatory effects of two NO donors, S-nitroso-N-acetyl-D, L-penicillamine (SNAP) and S-nitrosoglutathione (GSNO) on the early events in insulin signaling in rat skeletal myocytes. Skeletal muscle cells from 6-8 week old Sprague-Dawley rats were treated with SNAP or GSNO (25 ng/ml) in the presence or absence of glucose (25 mM) and insulin (100 nM). Cellular insulin receptor-beta levels and tyrosine phosphorylation in IRS-1 were significantly reduced, while serine phosphorylation in IRS-1 was significantly increased in these cells, when compared to the insulin-stimulated control. Reversal to near normal levels was achieved using the NO scavenger, 2-(4-carboxyphenyl)-4, 4, 5, 5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO). These data suggest that NO is a potent modulator of insulin-mediated signal transduction and may play a significa...
Molecular and cellular endocrinology, 1994
Nitric oxide, a radical generated by the enzyme nitric oxide synthase (iNOS), may be an important mediator of beta-cell damage in early insulin-dependent diabetes mellitus. We have investigated the molecular regulation of iNOS in insulin-producing RINm5F cells. The data obtained suggest that iNOS is maximally induced in these cells by a 6-h exposure to IL-1 beta or TNF-alpha + IFN-gamma, but not by endotoxin. iNOS mRNA degradation is rapid and it is not affected by IL-1 beta. Interestingly, NO seems to induce a negative feedback on iNOS expression, probably by decreasing iNOS transcription.
Understanding the in-vivo relevance of S -nitrosothiols in insulin action
Canadian Journal of Physiology and Pharmacology, 2012
Insulin sensitivity is maximal in the postprandial state, decreasing with a fasting period through a mechanism that is dependent on the integrity of the hepatic parasympathetic nerves/nitric oxide (NO) production and increased hepatic glutathione (GSH) levels. GSH and NO react to form S-nitrosoglutathione (GSNO), an S-nitrosothiol (RSNO) for which the in-vivo effects are still being determined. The goal of this study was to test the hypothesis that in-vivo administration of RSNOs, GSNO, or S-nitroso-N-acetylpenicillamine (SNAP) increases insulin sensitivity in fasted or fed-denervated animals, but not in fed animals, where full postprandial insulin sensitivity is achieved. Fasted, fed, or fed-denervated male Wistar rats were used as models for different insulin sensitivity conditions. The rapid insulin sensitivity test (RIST) was used to measure insulin-stimulated glucose disposal before and after drug administration (GSNO, SNAP, or 3-morpholinosydnonimine (SIN-1), intravenous (i.v....
The Open Cardiovascular Medicine Journal
Nitric oxide synthases (NOS) are the enzymes responsible for nitric oxide (NO) generation. NO is a reactive oxygen species as well as a reactive nitrogen species. It is a free radical which mediates several biological effects. It is clear that the generation and actions of NO under physiological and pathophysiological conditions are regulated and extend to almost every cell type and function within the circulation. In mammals 3 distinct isoforms of NOS have been identified: neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS). The important isoform in the regulation of insulin resistance (IR) is iNOS. Understanding the molecular mechanisms regulating the iNOS pathway in normal and hyperglycemic conditions would help to explain some of vascular abnormalities observed in type 2 diabetes mellitus (T2DM). Previous studies have reported increased myocardial iNOS activity and expression in heart failure (HF). This review considers the recent animal studies which focus on t...