Genetic Variants of<i>TCF7L2</i>Are Associated with Insulin Resistance and Related Metabolic Phenotypes in Taiwanese Adolescents and Caucasian Young Adults

Liu, Pi-Hua; Chang, Yi‐Cheng; Yin, Jiuli; Chen, Wei-Jen; Chang, Tien-Jyun; Kuo, Shan-Shan; Lee, Kuan-Ching; Hsiao, Po-Chang; Chiu, Ken C.; Chuang, Lee‐Ming

doi:10.1210/jc.2009-0609

Cited by 50 publications

(52 citation statements)

References 36 publications

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“…HOMA2-IR was significantly higher in patients with rs290487 C/C variant homozygote than those with T/T or T/C genotypes. This result was consistent with a previous study, which revealed that rs290487 C allele was significantly associated with increased IR in both Taiwanese and Caucasians (Chang et al, 2010;Liu et al, 2009). Since HD is characterized by very high IR compared to type 2 diabetes (Garcia-Compean et al, 2009), the association between TCF7L2 genetic variant and increased IR may help us to understand the mechanism of HD.…”

Section: Discussionsupporting

confidence: 93%

Impacts of TCF7L2 gene polymorphisms on the susceptibility of hepatogenous diabetes and hepatocellular carcinoma in cirrhotic patients

Ling

Dong

Geng

et al. 2013

Gene

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Section: Discussionsupporting

confidence: 93%

Impacts of TCF7L2 gene polymorphisms on the susceptibility of hepatogenous diabetes and hepatocellular carcinoma in cirrhotic patients

Ling

Dong

Geng

et al. 2013

Gene

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“…Accumulated β-catenin translocates to the nucleus, where it binds to TCF/LEF transcription factors to activate the transcription of Wnt-responsive genes involved in cell proliferation and differentiation [29]. Various studies have demonstrated an association of TCF7L2 variants with features of metabolic syndrome, including elevated systolic and diastolic blood pressure, increased triglyceride levels, and elevated uric acid [30,31]. Recently, the activation of Wnt/β-catenin signaling in skeletal muscle cells was reported to improve insulin sensitivity by decreasing intramyocellular lipid deposition via downregulation of SREBP-1c [19].…”

Section: Discussionmentioning

confidence: 99%

Exendin-4 Inhibits Hepatic Lipogenesis by Increasing β-Catenin Signaling

et al. 2016

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The aim of this study is to investigate whether the beneficial effect of exendin-4 on hepatic steatosis is mediated by β-catenin signaling. After the HepG2 human hepatoma cells were treated with PA for 24 hours, total triglycerides levels were increased in a dose-dependent manner, and the expression levels of perilipin family members were upregulated in cells treated with 400 μM PA. For our in vitro model of hepatic steatosis, HepG2 cells were treated with 400 μM palmitic acid (PA) in the presence or absence of 100 nM exendin-4 for 24 hours. PA increased the expression of lipogenic genes, such as sterol regulatory element-binding protein 1c (SREBP-1c), peroxisome proliferator-activated receptor gamma (PPARγ), stearoyl-CoA desaturase 1 (SCD1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) and triglyceride synthesis-involved genes, such as diacylglycerol acyltransferase 1 (DGAT1) and diacylglycerol acyltransferase 2 (DGAT2) in HepG2 cells, whereas exendin-4 treatment significantly prevented the upregulation of SREBP-1c, PPARγ, SCD1, FAS, ACC, DGAT1 and DGAT2. Moreover, exendin-4 treatment increased the expression of phosphorylated glycogen synthase kinase-3 beta (GSK-3β) in the cytosolic fraction and the expression of β-catenin and transcription factor 4 (TCF4) in the nuclear fraction. In addition, siRNA-mediated inhibition of β-catenin upregulated the expression of lipogenic transcription factors. The protective effects of exendin-4 on intracellular triglyceride content and total triglyceride levels were not observed in cells treated with the β-catenin inhibitor IWR-1. These data suggest that exendin-4 treatment improves hepatic steatosis by inhibiting lipogenesis via activation of Wnt/β-catenin signaling.

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“…The mechanism is uncertain, with some studies reporting that risk genotype is associated with defective insulin secretion (2,23–25). Some studies have reported an association with a decreased insulin action (8,26), and others have reported both (27). The present studies measured insulin secretion and insulin action in a large number of subjects with the TT genotype on three separate occasions and compared the results to those observed in carefully matched subjects with the CC genotype.…”

Section: Discussionmentioning

confidence: 99%

TCF7L2 Genotype and α-Cell Function in Humans Without Diabetes

et al. 2015

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The diabetes-associated allele in TCF7L2 increases the rate of conversion to diabetes; however, the mechanism by which this occurs remains elusive. We hypothesized that the diabetes-associated allele in this locus (rs7903146) impairs insulin secretion and that this defect would be exacerbated by acute free fatty acid (FFA)–induced insulin resistance. We studied 120 individuals of whom one-half were homozygous for the diabetes-associated allele TT at rs7903146 and one-half were homozygous for the protective allele CC. After a screening examination during which glucose tolerance status was determined, subjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, FFA was elevated by infusion of Intralipid plus heparin. On the other study day, subjects received the same amount of glycerol as present in the Intralipid infusion. β-Cell responsivity indices were estimated with the oral C-peptide minimal model. We report that β-cell responsivity was slightly impaired in the TT genotype group. Moreover, the hyperbolic relationship between insulin secretion and β-cell responsivity differed significantly between genotypes. Subjects also exhibited impaired suppression of glucagon after an oral challenge. These data imply that a genetic variant harbored within the TCF7L2 locus impairs glucose tolerance through effects on glucagon as well as on insulin secretion.

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Genetic Variants ofTCF7L2Are Associated with Insulin Resistance and Related Metabolic Phenotypes in Taiwanese Adolescents and Caucasian Young Adults

Abstract: These findings support an important role for T2D risk-conferring gene TCF7L2 in insulin resistance in both Taiwanese and Caucasian youth and underscore the emerging role of Wnt signaling in insulin resistance.

Cited by 50 publications

References 36 publications

Impacts of TCF7L2 gene polymorphisms on the susceptibility of hepatogenous diabetes and hepatocellular carcinoma in cirrhotic patients

Impacts of TCF7L2 gene polymorphisms on the susceptibility of hepatogenous diabetes and hepatocellular carcinoma in cirrhotic patients

Exendin-4 Inhibits Hepatic Lipogenesis by Increasing β-Catenin Signaling

TCF7L2 Genotype and α-Cell Function in Humans Without Diabetes

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