Hepatic expression of insulin-like growth factor-binding protein-1 (IGFBP-1) is rapidly and completely inhibited by insulin. The signalling pathway that mediates this effect of insulin requires the activation of phosphoinositide 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 B, 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.
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
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Satish PATEL, Jeroen VAN DER KAAY, Calum SUTHERLAND; 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. Biochem J 15 July 2002; 365 (2): 537–545. doi: https://doi.org/10.1042/bj20020266
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