title: Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat.
abstract: OBJECTIVE
  Glucokinase activators (GKAs) are currently being developed as new therapies for type 2 diabetes and have been shown to enhance beta cell survival and proliferation in vitro. Here, we report the effects of chronic GKA treatment on the development of hyperglycaemia and beta cell loss in the male Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes with severe obesity.
  
  
  METHODS
  Cell protection by GKA was studied in MIN6 and INS-1 cells exposed to hydrogen peroxide. Glucose homeostasis and beta cell mass were evaluated in ZDF rats dosed for 41 days with Cpd-C (a GKA) or glipizide (a sulfonylurea) as food admixtures at doses of approximately 3 and 10 mg kg(-1) day(-1).
  
  
  RESULTS
  Incubation of MIN6 and INS-1 832/3 insulinoma cell cultures with GKA significantly reduced cell death and impairment of intracellular NADH production caused by exposure to hydrogen peroxide. Progression from prediabetes (normoglycaemia and hyperinsulinaemia) to overt diabetes (hyperglycaemia and hypoinsulinaemia) was significantly delayed in male ZDF rats by in-feed treatment with Cpd-C, but not glipizide. Glucose tolerance, tested in the fifth week of treatment, was also significantly improved by Cpd-C, as was pancreatic insulin content and beta cell area. In a limited immunohistochemical analysis, Cpd-C modestly and significantly enhanced the rate of beta cell proliferation, but not rates of beta cell apoptosis relative to untreated ZDF rats.
  
  
  CONCLUSIONS
  These findings suggest that chronic activation of glucokinase preserves beta cell mass and delays disease in the ZDF rat, a model of insulin resistance and progressive beta cell failure.
authors.affiliation: Banyu Tsukuba Research Institute, Okubo, Tsukuba, Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Futamura
authors.forename: J
authors.initials: J
authors.lastname: Yao
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: R
authors.initials: R
authors.lastname: Bergeron
authors.forename: J-L
authors.initials: JL
authors.lastname: Tran
authors.forename: E
authors.initials: E
authors.lastname: Zycband
authors.forename: J
authors.initials: J
authors.lastname: Woods
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: Q
authors.initials: Q
authors.lastname: Shao
authors.forename: H
authors.initials: H
authors.lastname: Maruki-Uchida
authors.forename: H
authors.initials: H
authors.lastname: Goto-Shimazaki
authors.forename: R B
authors.initials: RB
authors.lastname: Langdon
authors.forename: M D
authors.initials: MD
authors.lastname: Erion
authors.forename: J
authors.initials: J
authors.lastname: Eiki
authors.forename: Y-P
authors.initials: YP
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D020536:Enzyme Activators / Q000494:pharmacology*; D005941:Glucokinase / Q000378:metabolism*; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D008297:Male; D051379:Mice; D051381:Rats; D011924:Rats, Zucker; D013450:Sulfones / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: D020536:Enzyme Activators; D007328:Insulin; D013450:Sulfones; D013830:Thiadiazoles; D005941:Glucokinase