title: Generation of mouse models for type 1 diabetes by selective depletion of pancreatic beta cells using toxin receptor-mediated cell knockout.
abstract: By using the toxin receptor-mediated cell knockout (TRECK) method, we have generated two transgenic (Tg) murine lines that model type 1 (insulin-dependent) diabetes. The first strain, C.B-17/Icr-Prkdc(scid)/Prkdc(scid)-INS-TRECK-Tg, carries the diphtheria toxin receptor (hDTR) driven by the human insulin gene promoter, while the other strain, C57BL/6-ins2(BAC)-TRECK-Tg, expresses hDTR cDNA under the control of the mouse insulin II gene promoter. With regard to the C.B-17/Icr-Prkdc(scid)/Prkdc(scid)-INS-TRECK-Tg strain, only one of three Tg strains exhibited proper expression of hDTR in pancreatic β cells. By contrast, hDTR was expressed in the pancreatic β cells of all four of the generated C57BL/6-ins2(BAC)-TRECK-Tg strains. Hyperglycemia, severe ablation of pancreatic β cells and depletion of serum insulin were observed within 3days after the administration of diphtheria toxin (DT) in these Tg mice. Subcutaneous injection of a suitable dosage of insulin was sufficient for recovery from hyperglycemia in all of the examined strains. Using the C.B-17/Icr-Prkdc(scid)/Prkdc(scid)-INS-TRECK-Tg model, we tried to perform regenerative therapeutic approaches: allogeneic transplantation of pancreatic islet cells from C57BL/6 and xenogeneic transplantation of CD34(+) human umbilical cord blood cells. Both approaches successfully rescued C.B-17/Icr-Prkdc(scid)/Prkdc(scid)-INS-TRECK-Tg mice from hyperglycemia caused by DT administration. The high specificity with which DT causes depletion in pancreatic β cells of these Tg mice is highly useful for diabetogenic research.
authors.affiliation: Mammalian Genetics Project, Department of Genome Medicine, Tokyo Metropolitan Institute of Medical Science, 2-1-6, Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. matsuoka-kn@igakuken.or.jp
authors.forename: Kunie
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Michiko
authors.initials: M
authors.lastname: Saito
authors.forename: Kosuke
authors.initials: K
authors.lastname: Shibata
authors.forename: Michiko
authors.initials: M
authors.lastname: Sekine
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shitara
authors.forename: Choji
authors.initials: C
authors.lastname: Taya
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.forename: Tsuneo A
authors.initials: TA
authors.lastname: Takahashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Kohno
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kikkawa
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yonekawa
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D036101:Cord Blood Stem Cell Transplantation; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology*; D004167:Diphtheria Toxin / Q000009:adverse effects* / Q000378:metabolism; D055786:Gene Knockout Techniques; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000473:pathology / Q000628:therapy; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D061385:Insulins / Q000008:administration & dosage / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
chemical_list: D018952:Antigens, CD34; D004167:Diphtheria Toxin; D061385:Insulins; D011956:Receptors, Cell Surface; D005947:Glucose
keywords: Allogeneic transplantation; Diabetes; Diphtheria toxin; Transgenic mice; Xenogeneic transplantation