The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing β-Cell Function and Hepatic Insulin Sensitivity

OBJECTIVE: In this study, we aimed to explore the mechanism by which TCF7L2 rs7903146 risk allele confers susceptibility to impaired glucose tolerance (IGT) or type 2 diabetes (T2D) in obese adolescents. RESEARCH DESIGN AND METHODS: The rs7903146 variant in the TCF7L2 gene was genotyped in a multiethnic cohort of 955 youths. All subjects underwent an oral glucose tolerance test with the use of the Oral Minimal Model to assess insulin secretion, and 33 subjects underwent a hyperinsulinemic-euglycemic clamp. In 307 subjects, a follow-up oral glucose tolerance test was repeated after 3.11 ± 2.36 years. RESULTS: The TCF7L2 rs7903146 risk allele was associated with higher 2-h glucose levels in Caucasians (P = 0.006) and African Americans (P = 0.009), and a trend was seen also in Hispanics (P = 0.072). Also, the T allele was associated with decreased β-cell responsivity and IGT (P < 0.05). Suppression of endogenous hepatic glucose production was lower in subjects with the risk variant (P = 0.006). Finally, the odds of showing IGT/T2D at follow-up were higher in subjects carrying the minor allele (odds ratio 2.224; 95% CI 1.370–3.612; P = 0.0012). CONCLUSIONS: The rs7903146 variant in the TCF7L2 gene increases the risk of IGT/T2D in obese adolescents by impairing β-cell function, and hepatic insulin sensitivity predicts the development of IGT/T2D over time.