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3 T3-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。在10 μ M浓度下，雌二醇增强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PI 3-激酶p85调节亚基的结合、Akt磷酸化和2-脱氧葡萄糖摄取<-8>，但在10 μ M浓度下抑制这些作用<-5>。浓度为10-5 M的雌二醇可增强胰岛素诱导的IRS-1丝氨酸磷酸化<307>，而c-Jun NH 2-末端激酶抑制剂可消除这种作用。此外，雌二醇的作用被废除的预处理与特定的雌激素受体拮抗剂，ICI 182，780。不透膜的雌二醇E2-BSA在10 μ M时不影响胰岛素诱导的Akt磷酸化<-8>，但在10 μ M时抑制它<-5>。此外，雌二醇在10 μ M时降低了质膜上雌激素受体a的数量<-8>，但在10 μ M时增加了它<-5>。与此相反，雌激素受体p的亚细胞分布并没有改变的治疗。这些结果表明，雌二醇以浓度特异性方式影响胰岛素的代谢作用，高浓度雌二醇通过c-Jun NH 2-末端激酶依赖性途径调节IRS-1在Ser^的磷酸化来抑制胰岛素信号传导<307>，并且雌激素受体α响应雌二醇的亚细胞再分布可以解释雌二醇的双重作用。

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.