Effects of 17[beta]-Estradiol and Androgen on Glucose Metabolism in Skeletal Muscle

• Published in: Endocrinology (Philadelphia) 2016-12, Vol.157 (12), p.4691-4705
• Main Authors: Inada, Akari, Fujii, Nobuharu L, Inada, Oogi, Higaki, Yasuki, Furuichi, Yasuro, Nabeshima, Yo-ichi
• Format: Article
• Language: English
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2016-1261

Diabetes develops predominantly in males in experimental models, and extensive evidence suggests that 17[beta]-estradiol (E2) modulates progression of diabetes in humans. We previously developed a severely diabetic transgenic (Tg) mouse model by [beta]-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+5[alpha]-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 [beta]-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+5[alpha]-DHT-treated female ICER-Tg mice showed an elevation of blood glucose without any decrease of [beta]-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 (5[alpha]-DHT) promotes insulin resistance in females, whereas E2 improves insulin sensitivity in severely diabetic male mice.