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Reduction in Tcf7l2 expression decreases diabetic susceptibility in mice.

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.

SUBMITTER: Yang H

PROVIDER: S-EPMC3372883 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Reduction in Tcf7l2 expression decreases diabetic susceptibility in mice.

Yang Hyekyung H Li Qing Q Lee Jong-Hwan JH Shu Yan Y

International journal of biological sciences 20120605 6

<h4>Objective</h4>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.<h4>Experimental design</h4>Tcf7l2 knockout (Tcf7l⁻/⁻) mice were generated. Because of the early mortality of Tcf7l2⁻/⁻ mice, we characterized the metabolic phenotypes of heterozygous ...[more]

PMID: 22719219

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Project description:BACKGROUND:Coronary artery disease (CAD) shares common risk factors with type 2 diabetes (T2DM). Variations in the transcription factor 7-like 2 (TCF7L2) gene, particularly rs7903146, increase T2DM risk. Potential links between genetic variants of the TCF7L2 locus and coronary atherosclerosis are uncertain. We therefore investigated the association between TCF7L2 polymorphisms and angiographically determined CAD in diabetic and non-diabetic patients. METHODOLOGY/PRINCIPAL FINDINGS:We genotyped TCF7L2 variants rs7903146, rs12255372, and rs11196205 in a cross-sectional study including 1,650 consecutive patients undergoing coronary angiography for the evaluation of established or suspected stable CAD. Significant CAD was diagnosed in the presence of coronary stenoses ?50%. Variant rs7903146 in the total study cohort was significantly associated with significant CAD (adjusted additive OR?=?1.29 [1.09-1.53]; p?=?0.003). This association was strong and significant in T2DM patients (n?=?393; OR?=?1.91 [1.32-2.75]; p?=?0.001) but not in non-diabetic subjects (OR?=?1.09 [0.90-1.33]; p?=?0.370). The interaction risk allele by T2DM was significant (p(interaction)?=?0.002), indicating a significantly stronger impact of the polymorphism on CAD in T2DM patients than in non-diabetic subjects. TCF7L2 polymorphisms rs12255372 and rs11196205 were also significantly associated with CAD in diabetic patients (adjusted additive OR?=?1.90 [1.31-2.74]; p?=?0.001 and OR?=?1.75 [1.22-2.50]; p?=?0.002, respectively). Further, haplotype analysis demonstrated that haplotypes including the rare alleles of all investigated variants were significantly associated with CAD in the whole cohort as well as in diabetic subjects (OR?=?1.22 [1.04-1.43]; p?=?0.013 and OR?=?1.67 [1.19-2.22]; p?=?0.003, respectively). CONCLUSIONS/SIGNIFICANCE:These results suggest that TCF7L2 variants rs7903146 rs12255372, and rs11196205 are significantly associated with angiographically diagnosed CAD, specifically in patients with T2DM. TCF7L2 therefore appears as a genetic link between diabetes and atherosclerosis.

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Reduction in Tcf7l2 expression decreases diabetic susceptibility in mice.

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Reduction in Tcf7l2 expression decreases diabetic susceptibility in mice.

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