ABSTRACT
Accumulating evidence suggests that oxidant signals might be integrally involved in the regulation of the insulin-signaling pathway. Treatment of IRtransfected Chinese hamster ovary cells with antioxidants such as N-acetyl-Lcysteine (NAC) or butylated hydroxyanisole inhibits insulin responsiveness, whereas partial inhibition of glutathione metabolism, which intracellularly induces a mild oxidative stress condition, stimulates IR tyrosine phosphorylation when measured in vitro.15 A similar increase in IR kinase activity is observed following cell treatment with hydrogen peroxide (H2O2).16,17 Moreover, oxidation of critical cysteine residues in the IR
β subunit results in the increase of its intrinsic tyrosine kinase activity, whereas low concentration of dithiothreitol inactivates the IR kinase, supporting the importance of oxidation of critical thiol groups in activation of the insulin-signaling pathway.15 Agents such as H2O2, Cu2+, and diamide that readily oxidize sulfhydryls to disulfides markedly enhance 3-O-methylglucose uptake in brown fat cells.1 IR has also been demonstrated to couple, via G
αi2, to the NADPH-dependent H2O2-generating system, which upon insulin stimulation produces H2O2 in 3T3-L1 adipocytes.2 Insulin-dependent H2O2 production is associated with a decreased protein tyrosine phosphatase (PTP) activity,18 which is also found essential for the activation of PI3-K.3 These findings suggest that redox signals are involved in the regulation of both the early tyrosine phosphorylation cascade and downstream insulin-signaling events.
