Insulin inhibits inducible nitric oxide synthase in skeletal muscle cells

Recent studies have shown that cytokines and endotoxins impair insulin-stim ulated glucose transport by activating the expression of inducible nitric o xide synthase (iNOS) and nitric oxide (NO) production in skeletal muscle ce lls. In this study, we investigated whether iNOS induction is modulated by insulin in L6 myocytes. Long term exposure of muscle cells to tumour necros is factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and lipopolysacch aride (LPS) greatly increased iNOS mRNA expression and NO production. Addit ion of insulin to the cytokine/LPS-treated muscle cells reduced (by similar to 40%) NO production. This inhibition was similar to that observed with t he synthetic glucocorticoid dexamethasone, a known inhibitor of iNOS in sev eral cell types. The combination of insulin and dexamethasone was more effe ctive than either agent alone in reducing NO production. Dexamethasone grea tly inhibited the effect of cytokines/LPS to induce cellular iNOS mRNA expr ession. In strong contrast, insulin failed to reduce iNOS mRNA expression u nder similar conditions. These results show that insulin is a novel inhibit or of iNOS-mediated NO production in skeletal muscle cells. Furthermore, ou r data indicate that unlike glucocorticoids, insulin does not inhibit NO pr oduction by suppression of iNOS gene transcription.