Li Xin, Cui Peng, Jiang Hong-Yuan, Guo Yan-Rong, Pishdari Bano, Hu Min, Feng Yi, Billig Håkan, Shao Ruijin
Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University 200011 Shanghai, China ; Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg 40530 Gothenburg, Sweden ; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases 200011 Shanghai, China.
Department of Integrative Medicine and Neurobiology, State Key Lab of Medical Neurobiology, Shanghai Medical College and Institute of Acupuncture Research (WHO Collaborating Center for Traditional Medicine), Institute of Brain Science, Fudan University 200032 Shanghai, China.
Am J Transl Res. 2015 Mar 15;7(3):574-86. eCollection 2015.
Conflicting results have been reported regarding whether or not insulin-regulated glucose transporter 4 (GLUT4) is expressed in human and rodent endometria. There is an inverse relationship between androgen levels and insulin-dependent glucose metabolism in women. Hyperandrogenemia, hyperinsulinemia, and insulin resistance are believed to contribute to endometrial abnormalities in women with polycystic ovary syndrome (PCOS). However, it has been unclear in previous studies if endometrial GLUT4 expression is regulated by androgen-dependent androgen receptors (ARs) and/or the insulin receptor/Akt/mTOR signaling network. In this study, we demonstrate that GLUT4 is expressed in normal endometrial cells (mainly in the epithelial cells) and is down-regulated under conditions of hyperandrogenemia in tissues from PCOS patients and in a 5α-dihydrotestosterone-induced PCOS-like rat model. Western blot analysis revealed reduced endometrial GLUT4 expression and increased AR expression in PCOS patients. However, the reduced GLUT4 level was not always associated with an increase in AR in PCOS patients when comparing non-hyperplasia with hyperplasia. Using a human tissue culture system, we investigated the molecular basis by which GLUT4 regulation in endometrial hyperplasia tissues is affected by metformin in PCOS patients. We show that specific endogenous organic cation transporter isoforms are regulated by metformin, and this suggests a direct effect of metformin on endometrial hyperplasia. Moreover, we demonstrate that metformin induces GLUT4 expression and inhibits AR expression and blocks insulin receptor/PI3K/Akt/mTOR signaling in the same hyperplasia human tissues. These findings indicate that changes in endometrial GLUT4 expression in PCOS patients involve the androgen-dependent alteration of AR expression and changes in the insulin receptor/PI3K/Akt/mTOR signaling network.
关于胰岛素调节的葡萄糖转运蛋白4（GLUT4）是否在人类和啮齿动物子宫内膜中表达，已有相互矛盾的研究结果报道。女性雄激素水平与胰岛素依赖的葡萄糖代谢之间存在负相关关系。高雄激素血症、高胰岛素血症和胰岛素抵抗被认为与多囊卵巢综合征（PCOS）女性的子宫内膜异常有关。然而，在先前的研究中，尚不清楚子宫内膜GLUT4表达是否受雄激素依赖的雄激素受体（ARs）和/或胰岛素受体/Akt/mTOR信号网络的调节。在本研究中，我们证明GLUT4在正常子宫内膜细胞（主要在上皮细胞中）表达，并且在PCOS患者组织以及5α-二氢睾酮诱导的PCOS样大鼠模型的高雄激素血症条件下表达下调。蛋白质印迹分析显示PCOS患者子宫内膜GLUT4表达降低而AR表达增加。然而，在比较非增生与增生的PCOS患者时，GLUT4水平降低并不总是与AR增加相关。使用人体组织培养系统，我们研究了二甲双胍影响PCOS患者子宫内膜增生组织中GLUT4调节的分子基础。我们表明特定的内源性有机阳离子转运体同工型受二甲双胍调节，这表明二甲双胍对子宫内膜增生有直接作用。此外，我们证明二甲双胍在相同的增生人体组织中诱导GLUT4表达并抑制AR表达，并阻断胰岛素受体/PI3K/Akt/mTOR信号传导。这些发现表明，PCOS患者子宫内膜GLUT4表达的变化涉及AR表达的雄激素依赖性改变以及胰岛素受体/PI3K/Akt/mTOR信号网络的变化。
