Physiological and pathophysiological roles of Tcf7l2 in pancreatic beta cells in a murine model

2014 Fiscal Year Final Research Report

• Project/Area Number: 25860741
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: The University of Tokyo
• Principal Investigator: TAKAMOTO ISEKI 東京大学, 医学部附属病院, 助教 (60431871)
• Research Collaborator: 窪田 直人 ; 中屋 恵三 ; 熊谷 勝義 ; 橋本 信嗣 ; 窪田 哲也 ; 井上 真理子 ; 梶原 栄二 ; 勝山 修行 ; 小畑 淳史 ; 桜井 賛孝 ; 岩本 真彦 ; 北村 忠弘 ; 植木 浩二郎 ; 門脇 孝
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 糖尿病 / インスリン分泌 / 膵β細胞 / Tcf7l2

Outline of Final Research Achievements

Common genetic variations of TCF7L2 are associated with type 2 diabetes. In this study, we investigated the roles of TCF7L2 expressed in the pancreatic beta cells in glucose homeostasis. DN mice were generated, in which expression of the dominant-negative form of Tcf7l2 was driven under a rat insulin promoter. The expression of the dominant-negative form of TCF7L2 from the embryonic stage in the pancreatic beta cells was associated with a reduction in beta cell area and pancreatic insulin content in the newborn mice, leading to impaired glucose tolerance with decreased insulin secretion in the adult stage. Especially, islets from the DN mice showed decreased gene expression of MafA, consistent with the deleterious effects of the dominant-negative form of Tcf7l2 on beta cell proliferation and insulin production. Thus, our findings suggest that TCF7L2 in the pancreatic beta cells plays a crucial role in glucose metabolism through regulation of the beta cell mass during development.

Free Research Field

糖尿病