Inada Akari, Fujii Nobuharu L, Inada Oogi, Higaki Yasuki, Furuichi Yasuro, Nabeshima Yo-Ichi
Laboratory of Molecular Life Science (A.I., Y.N.), Institute of Biomedical Research and Innovation, Kobe 650-0047, Japan; Department of Diabetes and Genes (A.I., O.I.), Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Health Promotion Sciences (N.L.F.), Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan; and Faculty of Sports and Health Science (Y.H.) and Institute for Physical Activity (Y.H.), Fukuoka University, Fukuoka 814-0180, Japan.
Endocrinology. 2016 Dec;157(12):4691-4705. doi: 10.1210/en.2016-1261. Epub 2016 Sep 21.
Diabetes develops predominantly in males in experimental models, and extensive evidence suggests that 17β-estradiol (E2) modulates progression of diabetes in humans. We previously developed a severely diabetic transgenic (Tg) mouse model by β-cell-specific overexpression of inducible cAMP early repressor (ICER) and found that male ICER-Tg mice exhibit sustained severe hyperglycemia, but female ICER-Tg mice gradually became normoglycemic with aging. This implies that differences in circulating androgen and E2 levels might influence skeletal muscle glucose uptake and glycemic status. Here we examined whether a decrease of androgen or E2 excess can improve muscle glucose uptake in hyperglycemic male ICER-Tg mice and, conversely, whether a decrease of E2 or androgen excess can elevate blood glucose levels and impair muscle glucose uptake in normoglycemic female ICER-Tg mice. We treated hyperglycemic male ICER-Tg mice with orchiectomy (ORX) or ORX+E2 pellet implantation and normoglycemic female ICER-Tg mice with ovariectomy (OVX) or OVX+5α-DHT pellet implantation to alter the androgen to E2 ratio. ORX+E2 treatment of male ICER-Tg mice caused a rapid drop in blood glucose via both a dramatic increase of β-cells and significantly improved muscle glucose uptake due to the induction of glucose transporter type 4 (GLUT4) expression and translocation of GLUT4 to the cell membrane. In contrast, OVX+5α-DHT-treated female ICER-Tg mice showed an elevation of blood glucose without any decrease of β-cells; instead, they showed decreased muscle glucose uptake due to decreased activation of serine/threonine-specific protein kinase AKT and GLUT4 expression. These findings suggest that androgen (5α-DHT) promotes insulin resistance in females, whereas E2 improves insulin sensitivity in severely diabetic male mice.
在实验模型中，糖尿病主要在雄性个体中发生，大量证据表明17β-雌二醇（E2）可调节人类糖尿病的进展。我们之前通过在β细胞特异性过表达诱导型cAMP早期阻遏物（ICER）构建了一种重度糖尿病转基因（Tg）小鼠模型，发现雄性ICER-Tg小鼠表现出持续的严重高血糖症，但雌性ICER-Tg小鼠随着年龄增长逐渐恢复正常血糖水平。这意味着循环雄激素和E2水平的差异可能会影响骨骼肌葡萄糖摄取和血糖状态。在此，我们研究了雄激素减少或E2过量是否能改善高血糖雄性ICER-Tg小鼠的肌肉葡萄糖摄取，反之，E2减少或雄激素过量是否会使正常血糖的雌性ICER-Tg小鼠血糖水平升高并损害肌肉葡萄糖摄取。我们对高血糖雄性ICER-Tg小鼠进行去势（ORX）或ORX+E2颗粒植入处理，对正常血糖的雌性ICER-Tg小鼠进行卵巢切除（OVX）或OVX+5α-双氢睾酮（DHT）颗粒植入处理，以改变雄激素与E2的比例。对雄性ICER-Tg小鼠进行ORX+E2处理导致血糖迅速下降，这是由于β细胞显著增加以及葡萄糖转运蛋白4（GLUT4）表达的诱导和GLUT4向细胞膜的转位，从而显著改善了肌肉葡萄糖摄取。相反，OVX+5α-DHT处理的雌性ICER-Tg小鼠血糖升高，β细胞数量未减少；相反，由于丝氨酸/苏氨酸特异性蛋白激酶AKT的激活减少和GLUT4表达降低，它们的肌肉葡萄糖摄取减少。这些发现表明，雄激素（5α-DHT）会促进雌性胰岛素抵抗，而E则可改善重度糖尿病雄性小鼠的胰岛素敏感性。
