New mouse model to study islet transplantation in insulin-dependent diabetes mellitus

Background. Islet transplantation studies with diabetic rodents frequently use treatment with diabetogens such as alloxan or streptozotocin to render hosts hyperglycemic. These chemicals produce unwanted toxic side effects, which complicate interpretations of damage produced by hyperglycemia versus direct toxin-induced damage. A mouse that spontaneously developed insulin-sensitive diabetes without beta-cell autoimmunity would provide an excellent vehicle for testing beta-cell replacement protocols. The Ins2(Akita) mutation disrupts normal insulin processing and causes a failure in secretion of mature insulins, which results in the early development of hyperglycemia. This report examines the insulin sensitivity of mice that carry Ins2(Akita) and their responsiveness to engraftment with syngeneic pancreatic islets. Methods. Ten-week-old C57BL/6J-Ins2(Akita/+) males were given I unit of insulin to determine insulin sensitivity. Also, 10-week-old, hyperglycemic B6-Ins2(Akita/+) received either 400 islets isolated from syngeneic C57BTL/6J males (n=7) or from allogeneic BALB/cJ males (n=5) under the renal capsule. These mice were followed for 8 weeks after engraftment or until remission of euglycemia. Nephrectomy of the graft-containing kidney was performed on mice that remained euglycemic. These mice were then followed for 2 weeks for return of hyperglycemia. Results. B6-Ins2(Akita/+) mice are insulin responsive. Insulin treatment of hyperglycemic B6-Ins2(Akita/+) males significantly lowered blood glucose values within 1 hr. In addition, B6-Ins2(Akita/+) recipients of syngeneic islet grafts reversed their diabetic state in less than 72 hr. These islet-engrafted mice remained normoglycemic until removal of the graft-containing kidney. Removal of the graft resulted in a return to hyperglycemia. Mice that received allogeneic grafts efficiently rejected the graft. Conclusions. Our data support the hypothesis that B6-Ins2(Akita/+) mice are insulin sensitive and provide an excellent model for islet transplantation studies. In addition, the reduced beta-cell mass and the absence of beta-cell autoimmunity, coupled to the fact that these mice also reject allografts, suggest that these mice may be useful for a variety of other applications, including testing functionality of human islets prepared for transplantation and perhaps also for exploring beta-cell restorative therapy using pancreatic islet stem cells.