title: Reversing the reduced level of endometrial GLUT4 expression in polycystic ovary syndrome: a mechanistic study of metformin action.
abstract: 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.
authors.affiliation: 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.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Peng
authors.initials: P
authors.lastname: Cui
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University 200011 Shanghai, China ; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases 200011 Shanghai, China.
authors.forename: Hong-Yuan
authors.initials: HY
authors.lastname: Jiang
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University 200011 Shanghai, China ; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases 200011 Shanghai, China.
authors.forename: Yan-Rong
authors.initials: YR
authors.lastname: Guo
authors.affiliation: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg 40530 Gothenburg, Sweden.
authors.forename: Bano
authors.initials: B
authors.lastname: Pishdari
authors.affiliation: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg 40530 Gothenburg, Sweden.
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg 40530 Gothenburg, Sweden ; 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg 40530 Gothenburg, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Billig
authors.affiliation: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg 40530 Gothenburg, Sweden.
authors.forename: Ruijin
authors.initials: R
authors.lastname: Shao
keywords: Glucose transporter 4; PCOS; androgen receptor; endometrium; insulin receptor; metformin