Cytokine-induced glucose uptake in skeletal muscle: redox regulation and the role of alpha-lipoic acid

Abstract

In L6 myotubes, glucose uptake stimulated by interferon (IFN)-gamma or lipopolysaccharides (LPS) and a combination of LPS, IFN-gamma, and tumor necrosis factor (TNF)-alpha was inhibited by the antioxidant pyrrolidinedithiocarbamate and potentiated in reduced glutathione (GSH)-deficient cells. Also, the stimulatory effect of LPS and IFN-gamma individually, and of a combination of LPS, IFN-gamma, and TNF-alpha, on glucose uptake was associated with an increased level of intracellular oxidants (dichlorofluorescein assay) and loss of intracellular GSH. Study of the individual effects of LPS, IFN-gamma, and TNF-alpha as well as of a combination of the three activators provided evidence against a role of nitric oxide in mediating the stimulatory effect of the above-mentioned agents on glucose uptake. We also observed that the insulin-mimetic nutrient alpha-lipoic acid (LA; R-enantiomer) is able to stimulate glucose uptake in cytokine-treated cells that are insulin resistant. This study shows that cytokine-induced glucose uptake in skeletal muscle cells is redox sensitive and that, under conditions of acute infection that is accompanied with insulin resistance, LA may have therapeutic implications in restoring glucose availability in tissues such as the skeletal muscle.