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1 The Upjohn Company Pharmaceutical Research and Development, Kalamazoo, MI, USA
2 Takeda Pharmaceuticals North America, Inc., Lincolnshire, IL, USA
* To whom correspondence should be addressed. E-mail: mkhan{at}tpna.com.
Thiazolidinediones may slow the progression of type 2 diabetes by preserving pancreatic 
cells. The effects of pioglitazone on structure and function of cells in KKA(y), C57BL/6J ob/ob, and C57BL/KsJ db/db mice (genetic models of type 2 diabetes) were
examined. Ob/ob (n = 7) and db/db (n = 9) mice were randomly assigned to pioglitazone 50-125mg/kg body weight per day in chow beginning at age 6-10 weeks. Control ob/ob
(n = 7) and db/db mice (n = 9) were fed chow without pioglitazone. KKA(y) mice (n = 15) were fed pioglitazone daily at doses of 62-144mg/kg body weight per day. Control
KKA(y) mice (n = 10) received chow without pioglitazone. Treatment continued until euthanasia at age 14-26 weeks. Blood was collected at baseline (before treatment) and
just prior to euthanasia and analyzed for glucose, glycosylated hemoglobin, and plasma insulin. Some of the splenic pancreas of each animal was resected, , and partially sectioned for light or electron microscopy. The remainder of the pancreas was assayed for insulin content. Compared to baseline and control groups, pioglitazone treatment significantly reduced blood glucose and glycosylated hemoglobin levels. Plasma insulin levels decreased significantly in ob/ob mice treated with pioglitazone. All groups treated with pioglitazone exhibited significantly greater B-cell granulation, evidence of reduced B-cell stress, and 1.5- to 15-fold higher levels of pancreatic insulin. The data from these
studies suggest comparable effects would be expected to slow the progression of type 2 diabetes, either delaying or possibly preventing progression to an insulin-dependent state.
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