Insulin regulation of hepatic insulin-like growth factor-binding protein-1 (IGFBP-1) gene expression and mammalian target of rapamycin (mTOR) signalling is impaired by the presence of hydrogen peroxide

Hepatic expression of insulin-like growth factor-binding protein-l (IGFBP-1) is rapidly and completely inhibited by insulin. The signalling pathway that mediates this effect of insulin requires the activation of phosphomositide 3-kinase (PI 3-kinase). Many of the cellular actions of insulin, including activation of PI 3-kinase, can be 'mimicked' by oxidative stresses, such as H2O2. In the present study, we demonstrate that H2O2 does not 'mimic' but rather antagonizes insulin repression of IGFBP-1 gene expression in H4IIE cells. This effect is accompanied by a decrease in the insulin-induced activation of mammalian target of rapamycin (mTOR)-dependent signalling. However, insulin-induced phosphorylation and regulation of protein kinase 13, glycogen synthase kinase-3 and FKHR (forkhead in rhabdomyosarcoma) are not affected by H2O2 in the same cells. In addition, H2O2 strongly activates the p42/p44 mitogen-activated protein kinases, but the presence of PD184352 (an inhibitor of this pathway) does not block the effect of H2O2 on IGFBP-1 gene expression. Our results support the view that the insulin-mediated repression of IGFBP-1 gene expression is partly mTOR-dependent, and demonstrate that H2O2 selectively antagonizes mTOR-dependent insulin action. The implications for the use of H2O2-generating agents as therapeutics for the treatment of insulin resistance, as well as the role of oxidative stress in the development of insulin resistance, are discussed.