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

Research Center for Genes, Environment, and Human Health, Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei 100, Taiwan.
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.31). 07/2009; 94(9):3575-82. DOI: 10.1210/jc.2009-0609
Source: PubMed

ABSTRACT The effect of TCF7L2 rs7903146 on glucose homeostasis is considered primarily due to impaired insulin secretion in European populations. Because we previously demonstrated that TCF7L2 rs290487 near the 3' end of TCF7L2 was significantly associated with type 2 diabetes (T2D) in Taiwanese subjects, we aimed to investigate potential mechanisms underlying the associations of rs290487 with T2D.
Eighteen single nucleotide polymorphisms (SNPs) were tested for association with glucose/insulin homeostasis as well as other quantitative metabolic phenotypes using the quantitative transmission disequilibrium test in 525 Taiwanese adolescent twin-pairs and siblings. The results were further replicated in 116 nondiabetic normotensive Caucasian young adults.
Among the 18 SNPs, rs290487 C allele was significantly associated with higher 60-, 90-, and 120-min glucose concentrations (P = 0.001, 0.01, and 0.02, respectively); higher 60- and 90-min insulin concentrations (P = 0.01 and 0.01, respectively); and a lower insulin sensitivity index (P = 0.04). No association was found for rs290487 with measures of insulin secretion. The rs290487 C allele was also associated with HOMA-IR (P = 0.005) and insulin sensitivity index (P = 0.01) in Caucasian young adults. Another SNP, rs10749127 C allele located in intron 4, was also associated with features of the metabolic syndrome, including elevated systolic (P = 0.02) and diastolic (P = 2.0 x 10(-4)) blood pressure, triglycerides (P = 7.0 x 10(-4)), and uric acid (P = 0.03). In a meta-analysis, the rs290487 C allele was confirmed to be associated with an increased risk of T2D (odds ratio, 1.11; 95% confidence interval, 1.03-1.19; P = 0.005) across East Asian populations.
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.

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    • "These findings have implicated altered Wnt signaling in impaired glucose metabolism and diabetes. While the associations between these genetic variants and type 2 diabetes appear as extremely robust, their effects on cellular insulin response are not understood (Liu et al., 2009; Rasmussen-Torvik et al., 2009). In principal, the biological effects imparted by the common polymorphisms are too small to be measurable in artificial cell systems and animal models. "
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