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

我们研究了雌激素改变3T3-L1脂肪细胞胰岛素信号的机制，以阐明女性2型糖尿病的发病机制。雌二醇(E2)处理不影响胰岛素诱导的胰岛素受体酪氨酸磷酸化。雌激素促进胰岛素诱导的胰岛素受体底物-1(IRS-1)酪氨酸磷酸化、IRS-1与PI3-激酶P85调节亚基的结合、Akt的磷酸化和10^~(-5)M处的2-脱氧葡萄糖摄取，但在10^~(-5)M时抑制这些作用。10~(-5)M的雌二醇促进胰岛素诱导的IRS-1在Ser^&lt；307和gt；的磷酸化，该作用可被c-juNH2-末端激酶抑制剂阻断。此外，雌激素的作用可被雌激素受体拮抗剂ICI182,780预先消除。膜不通透性雌二醇E_2-BSA不影响胰岛素诱导的Akt在10^~(-8)M的磷酸化，但在10^~(-5)M可抑制Akt的磷酸化。此外，雌二醇使10^~(-8)M质膜上雌激素受体a的含量减少，而在10~(？)这些结果表明，雌激素以浓度特异性的方式影响胰岛素的代谢作用，高浓度的雌二醇通过c-Jun NH2末端的激酶依赖途径调节IRS-1在Ser^&lt；307&gt；的磷酸化，从而抑制胰岛素信号转导；雌激素对雌激素受体a的亚细胞重新分布可能解释了雌二醇的双重作用。

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.