TCF7L2 involvement in estradiol- and progesterone-modulated islet and hepatic glucose homeostasis.
TCF7L2 involvement in estradiol- and progesterone-modulated islet and hepatic glucose homeostasis.
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TCF7L2 参与雌二醇和孕酮调节的胰岛和肝葡萄糖稳态
DOI：
10.1038/srep24859
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发表时间：
2016-04-25
影响因子：
4.6
通讯作者：
Li C
中科院分区：
文献类型：
--
作者：
Dong F;Ling Q;Ye D;Zhang Z;Shu J;Chen G;Fei Y;Li C
为评估葡萄糖稳态的关键调节因子TCF7L2在雌二醇（E2）和孕酮（P4）调节葡萄糖代谢过程中的作用，研究人员在上调和下调TCF7L2的情况下，用生理浓度的E2或P4处理小鼠胰岛素瘤细胞（MIN6）以及人肝癌细胞（hepG2和HUH7）。检测MIN6细胞中胰岛素/胰岛素原的分泌情况，同时评估肝癌细胞的葡萄糖摄取和生成情况。在基础状态和刺激状态下，E2均能增加胰岛素/胰岛素原的分泌，而P4仅在葡萄糖刺激状态下增加胰岛素/胰岛素原的分泌。研究观察到E2和P4对胰岛葡萄糖代谢的调节存在拮抗作用，且可能具有浓度依赖性。经E2或P4处理后，胰岛素/胰岛素原的分泌与TCF7L2蛋白表达呈正相关。当TCF7L2基因沉默时，E2或P4促进胰岛素/胰岛素原分泌的作用显著减弱。在糖毒性条件下，过表达TCF7L2可增加胰岛素分泌及加工。在肝癌细胞中，暴露于E2或P4会提高TCF7L2的表达，增强胰岛素信号通路活性（pAKT/pGSK），降低磷酸烯醇式丙酮酸羧激酶（PEPCK）的表达，进而增加胰岛素刺激的葡萄糖摄取，并减少葡萄糖生成。沉默TCF7L2则会消除E2或P4的上述作用。综上所述，TCF7L2可调节E2或P4对胰岛和肝脏葡萄糖代谢的调控。该研究结果对孕期葡萄糖稳态具有重要意义。
To evaluate the role of TCF7L2, a key regulator of glucose homeostasis, in estradiol (E2) and progesterone (P4)-modulated glucose metabolism, mouse insulinoma cells (MIN6) and human liver cancer cells (hepG2 and HUH7) were treated with physiological concentrations of E2 or P4 in the up- and down-regulation of TCF7L2. Insulin/proinsulin secretion was measured in MIN6 cells, while glucose uptake and production were evaluated in liver cancer cells. E2 increased insulin/proinsulin secretion under both basal and stimulated conditions, whereas P4 increased insulin/proinsulin secretion only under glucose-stimulated conditions. An antagonistic effect, possibly concentration-dependent, of E2 and P4 on the regulation of islet glucose metabolism was observed. After E2 or P4 treatment, secretion of insulin/proinsulin was positively correlated with TCF7L2 protein expression. When TCF7L2 was silenced, E2- or P4-promoted insulin/proinsulin secretion was significantly weakened. Under glucotoxicity conditions, overexpression of TCF7L2 increased insulin secretion and processing. In liver cancer cells, E2 or P4 exposure elevated TCF7L2 expression, enhanced the activity of insulin signaling (pAKT/pGSK), reduced PEPCK expression, subsequently increased insulin-stimulated glucose uptake and decreased glucose production. Silencing TCF7L2 eliminated effects of E2 or P4. In conclusion, TCF7L2 regulates E2- or P4-modulated islet and hepatic glucose metabolism. The results have implications for glucose homeostasis in pregnancy.