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Generation of mouse models for type 1 diabetes by selective depletion of pancreatic beta cells using toxin receptor-mediated cell knockout

Matsuoka, Kunie, Saito, Michiko, Shibata, Kosuke, Sekine, Michiko, Shitara, Hiroshi, Taya, Choji, Zhang, Xiaohong, Takahashi, Tsuneo A., Kohno, Kenji, Kikkawa, Yoshiaki, Yonekawa, Hiromichi
Biochemical and biophysical research communications 2013 v.436 pp. 400-405
animal models, blood cells, blood serum, complementary DNA, genes, genetically modified organisms, humans, hyperglycemia, insulin, insulin-dependent diabetes mellitus, islets of Langerhans, mice, subcutaneous injection, umbilical cord
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-Prkdcscid/Prkdcscid-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-Prkdcscid/Prkdcscid-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-Prkdcscid/Prkdcscid-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-Prkdcscid/Prkdcscid-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.