Article

Diabetologia

, Volume 57, Issue 3, pp 542-553

First online:

TCF7L2 in mouse pancreatic beta cells plays a crucial role in glucose homeostasis by regulating beta cell mass

  • Iseki TakamotoAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of TokyoTranslational Systems Biology and Medicine Initiative (TSBMI), The University of TokyoDivision of Applied Nutrition, National Institute of Health and Nutrition
  • , Naoto KubotaAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of TokyoTranslational Systems Biology and Medicine Initiative (TSBMI), The University of TokyoDivision of Applied Nutrition, National Institute of Health and NutritionLaboratory for Metabolic Homeostasis, RIKEN Center for Integrative Medical Sciences Email author 
  • , Keizo NakayaAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo
  • , Katsuyoshi KumagaiAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of TokyoLaboratory Animal Research Center, Tokyo Medical University
  • , Shinji HashimotoAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo
  • , Tetsuya KubotaAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of TokyoDivision of Applied Nutrition, National Institute of Health and NutritionLaboratory for Metabolic Homeostasis, RIKEN Center for Integrative Medical SciencesDivision of Cardiovascular Medicine, Toho University, Ohashi Hospital
  • , Mariko InoueAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of TokyoDivision of Applied Nutrition, National Institute of Health and Nutrition
  • , Eiji KajiwaraAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo
  • , Hisayuki KatsuyamaAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo
    • , Atsushi ObataAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo
    • , Yoshitaka SakuraiAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo
    • , Masahiko IwamotoAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo
    • , Tadahiro KitamuraAffiliated withMetabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University
    • , Kohjiro UekiAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of TokyoTranslational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo
    • , Takashi KadowakiAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of TokyoTranslational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo Email author 

Abstract

Aims/hypothesis

Common genetic variations of the transcription factor 7-like 2 gene (encoded by TCF7L2), one of the T cell factor/lymphoid enhancer-binding factor transcription factors for the converging wingless-type MMTV integration site family (Wnt)/β-catenin signalling pathway, are known to be associated with type 2 diabetes. Individuals with at-risk alleles of TCF7L2 exhibit impaired insulin secretion. Although previous studies using animal models have revealed the existence of a relationship between the Wnt/β-catenin signalling pathway and glucose homeostasis, it remains unclear whether TCF7L2 in the pancreatic beta cells might be causally involved in insulin secretion in vivo. In this study, we investigated the role of TCF7L2 expressed in the pancreatic beta cells in glucose homeostasis.

Methods

Three independent groups of genetically engineered mice (DN mice) were generated, in which expression of the dominant-negative form of Tcf7l2 was driven under a rat insulin promoter. Phenotypes of both adult and newborn mice were evaluated. The levels of genes and proteins expressed in isolated islets were determined by reverse transcription-quantitative PCR and western blot analysis, respectively.

Results

Adult DN mice showed impaired glucose tolerance and decreased insulin secretion in both oral and intraperitoneal glucose tolerance tests. Marked reduction of the beta cell area and whole-pancreas insulin content was observed in both the adult and newborn DN mice. Islets from the DN mice showed decreased gene expressions of Ccnd1, Ccnd2, Irs1, Irs2, Ins1, Ins2 and Mafa, consistent with the deleterious effects of the dominant-negative form of Tcf7l2 on beta cell proliferation and insulin production.

Conclusions/interpretation

TCF7L2 expressed in the pancreatic beta cells plays a crucial role in glucose metabolism through regulation of the beta cell mass.

Keywords

Beta cell proliferation Dominant-negative form Insulin production Insulin secretion TCF7L2 Wnt/β-catenin signalling