title: Critical role of c-Kit in beta cell function: increased insulin secretion and protection against diabetes in a mouse model.
abstract: OBJECTIVE
  The receptor tyrosine kinase, c-Kit, and its ligand, stem cell factor, control a variety of cellular processes, including pancreatic beta cell survival and differentiation as revealed in c-Kit                            (                               Wv                            ) mice, which have a point mutation in the c-Kit allele leading to loss of kinase activity and develop diabetes. The present study further investigated the intrinsic role of c-Kit in beta cells, especially the underlying mechanisms that influence beta cell function.
  
  
  METHODS
  We generated a novel transgenic mouse model with c-KIT overexpression specifically in beta cells (c-KitβTg) to further examine the physiological and functional roles of c-Kit in beta cells. Isolated islets from these mice were used to investigate the underlying molecular pathway of c-Kit in beta cells. We also characterised the ability of c-Kit to protect animals from high-fat-diet-induced diabetes, as well as to rescue c-Kit                            (                               Wv                            ) mice from early onset of diabetes.
  
  
  RESULTS
  c-KitβTg mice exhibited improved beta cell function, with significantly improved insulin secretion, and increased beta cell mass and proliferation in response to high-fat-diet-induced diabetes. c-KitβTg islets exhibited upregulation of: (1) insulin receptor and IRSs; (2) Akt and glycogen synthase kinase 3β phosphorylation; and (3) transcription factors important for islet function. c-KIT overexpression in beta cells also rescued diabetes observed in c-Kit                            (                               Wv                            ) mice.
  
  
  CONCLUSIONS
  These findings demonstrate that c-Kit plays a direct protective role in beta cells, by regulating glucose metabolism and beta cell function. c-Kit may therefore represent a novel target for treating diabetes.
authors.affiliation: Victoria Research Laboratories, Room A5-140, 800 Commissioners Road East, London, ON, Canada, N6C 2V5.
authors.forename: Z C
authors.initials: ZC
authors.lastname: Feng
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: B A
authors.initials: BA
authors.lastname: Turco
authors.forename: M
authors.initials: M
authors.lastname: Riopel
authors.forename: S P
authors.initials: SP
authors.lastname: Yee
authors.forename: R
authors.initials: R
authors.lastname: Wang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D011972:Receptor, Insulin