title: β-cell induction in vivo in severely diabetic male mice by changing the circulating levels and pattern of the ratios of estradiol to androgens.
abstract: Previously we have generated transgenic (Tg) mice developing severe diabetes early in life with a profound depletion of β-cells with β-cell-directed expression of inducible cAMP early repressor-Iγ. Only male mice continue to demonstrate hyperglycemia throughout life. To investigate this sexual dimorphism, we treated severely diabetic male Tg mice with orchiectomy (ORX) or 17β-estradiol (E2) pellet implantation alone or in combination with ORX and E2-implantation to change the circulating levels and patterns of the ratio of estradiol to androgens. In the Tg-ORX group, the blood-glucose levels decreased to a certain level within several weeks but never reached the female Tg-control level. In contrast, the Tg-ORX+E2 or Tg-E2 group showed a more rapid drop in blood glucose to the basal level with a substantial increase in β-cells, thus preventing the occurrence of severe diabetes in the male mice. The β-cells, not only within islet but also in and adjacent to ducts and scattered β-cell clusters, were strongly induced by 1 week after treatment, and the islet morphology dramatically changed. Enhanced β-cell induction in the ducts occurred concomitantly with markedly increased levels of pancreatic duodenal homeobox-1 and related transcription factors. The glucose-lowering and β-cell-increasing effects were independent of the age at which the treatment is started. These data provide evidence that the circulating level of E2 and the ratio of E2 to T greatly affect the blood glucose levels, the β-cell induction, and the islet morphology in diabetic male Tg mice. This novel mechanism offers great potential for developing strategies to increase the number of β-cells in vivo.
authors: Departments of Diabetes and Genes and Advanced Medical Initiatives (A.I., O.I., K.F.), Developmental Molecular Anatomy (T.I.), and Pathophysiological and Experimental Pathology (HY.F., K.S.), and Medical Institute of Bioregulation (K.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Department of Health Promotion Sciences (N.L.F.), Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan.
authors: Akari
authors: A
authors: Inada
authors: Oogi
authors: O
authors: Inada
authors: Nobuharu L
authors: NL
authors: Fujii
authors: Kei
authors: K
authors: Fujishima
authors: Tetsuichiro
authors: T
authors: Inai
authors: Hiroshi
authors: H
authors: Fujii
authors: Katsuo
authors: K
authors: Sueishi
authors: Kotoku
authors: K
authors: Kurachi
mesh_terms: D000728:Androgens / Q000097:blood* / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000235:genetics / Q000503:physiopathology*; D004958:Estradiol / Q000097:blood* / Q000494:pharmacology; D005260:Female; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009919:Orchiectomy; D012720:Severity of Illness Index
chemical_list: D000728:Androgens; D001786:Blood Glucose; C497411:Crem protein, mouse; D051786:Cyclic AMP Response Element Modulator; D004958:Estradiol