The molecular mechanism by which FoxO1 regulates islet vascularization and compensative beta cell proliferation

2011 Fiscal Year Final Research Report

• Project/Area Number: 22790843
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Metabolomics
• Research Institution: Gunma University
• Principal Investigator: HASHIMOTO Hiromi 群馬大学, 生体調節研究所, 助手 (30323372)
• Project Period (FY): 2010 – 2011
• Keywords: FoxO1 / 糖尿病 / インスリン

Research 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 . 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 . cell mass, which is associated with decreased Pdx1 and MafA in . cells. We also observed that TG mice have islet hypervascularities due to increased VEGF-A expression in . cells. We performed chromatin immunoprecipitation (ChIP) assays and showed that FoxO1 binds to the VEGF-A promoter. We also showed in luciferase assays that FoxO1 regulates VEGF-A transcription in . cells. When FoxO1 is over expressed by adenovirus, VEGF-A mRNA level was increased in .TC3 cells. Despite severe reduction of . cells, plasma insulin levels and blood glucose levels as well as glucose tolerance were marginally impaired. We suppose this is due to increased VEGF-A expression and increased islets vascularity in TG mice. We propose that FoxO1 in pancreas plays important roles in the regulation of glucose metabolism.

Research Products

• [Journal Article] FoxO1 Gain of Function in the Pancreas Causes Glucose Intolerance, Polycystic Pancreas, and Islet Hypervascularization (2012)
  • Author(s): Kikuchi O, Kobayashi M, Amano K, Sasaki T, Kitazumi T, Kim H-J, Lee Y-S, Yokota-Hashimoto H, Kitamura Y-I, Kitamura T.
  • Journal Title: PLoS ONE Volume: 7 Pages: e32249
  • Peer Reviewed