| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
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^<-8> M, but inhibited these effects at 10^<-5> M. A concentration of 10-5 M estradiol enhanced insulin-induced phosphorylation of IRS-1 at Ser^<307>, 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^<-8> M, but inhibited it at 10^<-5> M. Furthermore, estradiol decreased the amount of estrogen receptor a at the plasma membrane at 10^<-8> M, but increased it at 10^<-5> 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^<307> 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.
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