Int J Biol Sci 2012; 8(6):791-801. doi:10.7150/ijbs.4568 This issue

Research Paper

Reduction in Tcf7l2 Expression Decreases Diabetic Susceptibility in Mice

Hyekyung Yang1, Qing Li1, Jong-Hwan Lee2, Yan Shu1✉

1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, USA.
2. Department of Veterinary Anatomy, College of Veterinary Medicine, Konkuk University, Seoul 143-701, Korea.

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Citation:
Yang H, Li Q, Lee JH, Shu Y. Reduction in Tcf7l2 Expression Decreases Diabetic Susceptibility in Mice. Int J Biol Sci 2012; 8(6):791-801. doi:10.7150/ijbs.4568. Available from https://www.ijbs.com/v08p0791.htm

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Abstract

Objective: The WNT signaling pathway effector gene TCF7L2 has been associated with an increased risk of type 2 diabetes. However, it remains unclear how this gene affects diabetic pathogenesis. The goal of this study was to investigate the effects of Tcf7l2 haploinsufficiency on metabolic phenotypes in mice.

Experimental Design: Tcf7l2 knockout (Tcf7l-/-) mice were generated. Because of the early mortality of Tcf7l2-/- mice, we characterized the metabolic phenotypes of heterozygous Tcf7l2+/- mice in comparison to the wild-type controls. The mice were fed a normal chow diet or a high fat diet (HFD) for 9 weeks.

Results: The Tcf7l2+/- mice showed significant differences from the wild-type mice with regards to body weight, fasting glucose and insulin levels. Tcf7l2+/- mice displayed improved glucose tolerance. In the liver of Tcf7l2+/- mice fed on the HFD, reduced lipogenesis and hepatic triglyceride levels were observed when compared with those of wild-type mice. Furthermore, the Tcf7l2+/- mice fed on the HFD exhibited decreased peripheral fat deposition. Immunohistochemistry in mouse pancreatic islets showed that endogenous expression of Tcf7l2 was upregulated in the wild-type mice, but not in the Tcf7l2+/- mice, after feeding with the HFD. However, the haploinsufficiency of Tcf7l2 in mouse pancreatic islets resulted in little changes in glucose-stimulated insulin secretion.

Conclusion: These results suggest that decreased expression of Tcf7l2 confers reduction of diabetic susceptibility in mice via regulation on the metabolism of glucose and lipid.

Keywords: Tcf7l2, diabetes, high fat diet, glucose tolerance, gluconeogenesis, hepatic steatosis.