title: FoxO1 gain of function in the pancreas causes glucose intolerance, polycystic pancreas, and islet hypervascularization.
abstract: Genetic studies revealed that the ablation of insulin/IGF-1 signaling in the pancreas causes diabetes. FoxO1 is a downstream transcription factor of insulin/IGF-1 signaling. We previously reported that FoxO1 haploinsufficiency restored β cell mass and rescued diabetes in IRS2 knockout mice. However, it is still unclear whether FoxO1 dysregulation in the pancreas could be the cause of diabetes. To test this hypothesis, we generated transgenic mice overexpressing constitutively active FoxO1 specifically in the pancreas (TG). TG mice had impaired glucose tolerance and some of them indeed developed diabetes due to the reduction of β cell mass, which is associated with decreased Pdx1 and MafA in β cells. We also observed increased proliferation of pancreatic duct epithelial cells in TG mice and some mice developed a polycystic pancreas as they aged. Furthermore, TG mice exhibited islet hypervascularities due to increased VEGF-A expression in β cells. We found FoxO1 binds to the VEGF-A promoter and regulates VEGF-A transcription in β cells. We propose that dysregulation of FoxO1 activity in the pancreas could account for the development of diabetes and pancreatic cysts.
authors.affiliation: Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kikuchi
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Kosuke
authors.initials: K
authors.lastname: Amano
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kitazumi
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Yong-Soo
authors.initials: YS
authors.lastname: Lee
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yokota-Hashimoto
authors.forename: Yukari-Ido
authors.initials: YI
authors.lastname: Kitamura
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003560:Cysts / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000502:physiology*; D018149:Glucose Intolerance / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007515:Islets of Langerhans / Q000098:blood supply / Q000473:pathology*; D051473:Maf Transcription Factors, Large / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism*; D010182:Pancreatic Diseases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D018398:Homeodomain Proteins; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; C084010:pancreatic and duodenal homeobox 1 protein