Aspirin attenuates insulin resistance in muscle of diet-induced obese rats by inhibiting inducible nitric oxide synthase production and S-nitrosylation of IRbeta/IRS-1 and Akt.

AIM/HYPOTHESIS: 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)-beta, 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.

METHODS: 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 IRbeta/IRS-1 and Akt was investigated using the biotin switch method.

RESULTS: iNOS protein levels increased in the muscle of diet-induced obese rats, associated with an increase in S-nitrosylation of IRbeta, 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 IkappaB kinase beta 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.

CONCLUSIONS/INTERPRETATION: Our data demonstrate that aspirin treatment not only reduces iNOS protein levels, but also S-nitrosylation of IRbeta, 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.