The rs7903146 variant in the tcf7l2 gene increases the risk of prediabetes/type 2 diabetes in obese adolescents by impairing b-cell function and hepatic insulin sensitivity

• Published in: Diabetes care Vol. 40; no. 8; p. 1082
• Main Authors: Cropano, Catrina, Santoro, Nicola, Groop, Leif, Man, Chiara Dalla, Cobelli, Claudio, Galderisi, Alfonso, Kursawe, Romy, Pierpont, Bridget, Goffredo, Martina, Caprio, Sonia
• Format: Journal Article
• Language: English
• Published: 01.08.2017
• Subjects: Clinical Medicine; Endocrinology and Diabetes; Endokrinologi och diabetes; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap
• ISSN: 0149-5992
• DOI: 10.2337/dc17-0290

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 6 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 trendwas seen also in Hispanics (P = 0.072). Also, the T allele was associated with decreased b-cell responsivity and IGT (P < 0.05). Suppression of endogenous hepatic glucose productionwas 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 b-cell function, and hepatic insulin sensitivity predicts the development of IGT/T2D over time.