Date: 03 Sep 2009
Aspirin attenuates insulin resistance in muscle of diet-induced obese rats by inhibiting inducible nitric oxide synthase production and S-nitrosylation of IRβ/IRS-1 and Akt
High-dose aspirin treatment improves fasting and postprandial hyperglycaemia in patients with type 2 diabetes, as well as in animal models of insulin resistance associated with obesity and sepsis. In this study, we investigated the effects of aspirin treatment on inducible nitric oxide synthase (iNOS)-mediated insulin resistance and on S-nitrosylation of insulin receptor (IR)-β, IRS-1 and protein kinase B (Akt) in the muscle of diet-induced obese rats and also in iNos (also known as Nos2)−/− mice on high fat diet.
Aspirin (120 mg kg−1 day−1 for 2 days) or iNOS inhibitor (L-NIL; 80 mg/kg body weight) were administered to diet-induced obese rats or mice and iNOS production and insulin signalling were investigated. S-nitrosylation of IRβ/IRS-1 and Akt was investigated using the biotin switch method.
iNOS protein levels increased in the muscle of diet-induced obese rats, associated with an increase in S-nitrosylation of IRβ, IRS-1 and Akt. These alterations were reversed by aspirin treatment, in parallel with an improvement in insulin signalling and sensitivity, as measured by insulin tolerance test and glucose clamp. Conversely, while aspirin reversed the increased phosphorylation of IκB kinase β and c-Jun amino-terminal kinase, as well as IRS-1 serine phosphorylation in diet-induced obese rats and iNos −/− mice on high-fat diet, these alterations were not associated with the improvement of insulin action induced by this drug.
Our data demonstrate that aspirin treatment not only reduces iNOS protein levels, but also S-nitrosylation of IRβ, IRS-1 and Akt. These changes are associated with improved insulin resistance and signalling, suggesting a novel mechanism of insulin sensitisation evoked by aspirin treatment.
Hundal RS, Petersen KF, Mayerson AB et al (2002) Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest 109:1321–1326PubMed
Kim JK, Kim YJ, Fillmore JJ et al (2001) Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 108:437–446PubMed
Wang Z, Brecher P (1999) Salicylate inhibition of extracellular signal-regulated kinases and inducible nitric oxide synthase. Hypertension 34:1259–1264PubMed
Jaffrey SR, Snyder SH (2001) The biotin switch method for the detection of S-nitrosylated proteins. Sci STKE 2001: PL1
Rohl M, Pasparakis M, Baudler S et al (2004) Conditional disruption of IkappaB kinase 2 fails to prevent obesity-induced insulin resistance. J Clin Invest 113:474–481PubMed
Jiang G, Dallas-Yang Q, Liu F, Moller DE, Zhang BB (2003) Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. J Biol Chem 278:180–186CrossRefPubMed
Taylor BS, Geller DA (2000) Molecular regulation of the human inducible nitric oxide synthase (iNOS) gene. Shock 13:413–424PubMed
- Aspirin attenuates insulin resistance in muscle of diet-induced obese rats by inhibiting inducible nitric oxide synthase production and S-nitrosylation of IRβ/IRS-1 and Akt
Volume 52, Issue 11 , pp 2425-2434
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Insulin resistance
- Industry Sectors
- Author Affiliations
- 1. FCM-UNICAMP, Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, Campinas, São Paulo, 13083-887, Brazil