Clarification of the mechanism of estrogen-induced regulation of insulin sensitivity in the pathogenesis of type 2 diabetes in female

We investigated the mechanisms by which estrogen alters insulin signaling in 3T3-L1 adipocytes to clarify the pathogenesis of type 2 diabetes in female. Treatment with estradiol (E2) did not affect insulin-induced tyrosine phosphorylation of insulin receptor. Estradiol enhanced insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), association of IRS-1 with p85 regulatory subunit of PI3-kinase, phosphorylation of Akt, and 2-deoxyglucose uptake at 10^ M, but inhibited these effects at 10^ M. A concentration of 10-5 M estradiol enhanced insulin-induced phosphorylation of IRS-1 at Ser^, which was abolished by treatment with a c-Jun NH2-terminal kinase inhibitor. In addition, the effect of estradiol was abrogated by pretreatment with a specific estrogen receptor antagonist, ICI182,780. Membrane-impermeable estradiol, E2-BSA, did not affect the insulin-induced phosphorylation of Akt at 10^ M, but inhibited it at 10^ M. Furthermore, estradiol decreased the amount of estrogen receptor a at the plasma membrane at 10^ M, but increased it at 10^ M. In contrast, the subcellular distribution of estrogen receptor p was not altered by the treatment. These results indicate that estradiol affects the metabolic action of insulin in a concentration-specific manner, that high concentrations of estradiol inhibited insulin signaling via modulating phosphorylation of IRS-1 at Ser^ via a c-Jun NH2-terminal kinase-dependent pathway, and that the subcellular redistribution of estrogen receptor a in response to estradiol may explain the dual effect of estradiol.