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Diabetologia
Published in: Diabetologia 3/2014

01-03-2014 | Article

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

Authors: Iseki Takamoto, Naoto Kubota, Keizo Nakaya, Katsuyoshi Kumagai, Shinji Hashimoto, Tetsuya Kubota, Mariko Inoue, Eiji Kajiwara, Hisayuki Katsuyama, Atsushi Obata, Yoshitaka Sakurai, Masahiko Iwamoto, Tadahiro Kitamura, Kohjiro Ueki, Takashi Kadowaki

Published in: Diabetologia | Issue 3/2014

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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.
Appendix
Available only for authorised users
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Metadata
Title
TCF7L2 in mouse pancreatic beta cells plays a crucial role in glucose homeostasis by regulating beta cell mass
Authors
Iseki Takamoto
Naoto Kubota
Keizo Nakaya
Katsuyoshi Kumagai
Shinji Hashimoto
Tetsuya Kubota
Mariko Inoue
Eiji Kajiwara
Hisayuki Katsuyama
Atsushi Obata
Yoshitaka Sakurai
Masahiko Iwamoto
Tadahiro Kitamura
Kohjiro Ueki
Takashi Kadowaki
Publication date
01-03-2014
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 3/2014
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-013-3131-6

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