title: Effects of 17β-Estradiol and Androgen on Glucose Metabolism in Skeletal Muscle.
abstract: 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.
authors.affiliation: 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.
authors.forename: Akari
authors.initials: A
authors.lastname: Inada
authors.affiliation: 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.
authors.forename: Nobuharu L
authors.initials: NL
authors.lastname: Fujii
authors.affiliation: 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.
authors.forename: Oogi
authors.initials: O
authors.lastname: Inada
authors.affiliation: 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.
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Higaki
authors.affiliation: 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.
authors.forename: Yasuro
authors.initials: Y
authors.lastname: Furuichi
authors.affiliation: 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.
authors.forename: Yo-Ichi
authors.initials: YI
authors.lastname: Nabeshima
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009919:Orchiectomy; D010052:Ovariectomy
chemical_list: D001786:Blood Glucose; D051275:Glucose Transporter Type 4; C495693:Slc2a4 protein, mouse; D013196:Dihydrotestosterone; D004958:Estradiol; D005947:Glucose