Journal
DIABETES CARE
Volume 40, Issue 8, Pages 1082-1089Publisher
AMER DIABETES ASSOC
DOI: 10.2337/dc17-0290
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-111038, R01-HD-028016, DK-045735]
- Progetti di Ricerca di Ateneo [CPDA145405/14]
- American Heart Association [13SDG14640038, 16IRG27390002]
- Allen Foundation award
- International Society for Pediatric and Adolescent Diabetes
- National Center for Advancing Translational Sciences, a component of the National Institutes of Health
- National Institutes of Health Roadmap for Medical Research Clinical and Translational Science Awards [UL1-RR-024139]
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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 hyper-insulinemic-euglycemic clamp. In 307 subjects, a follow-up oral glucose tolerance test was repeated after 3.11 62.3 +/- 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 beta-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 beta-cell function, and hepatic insulin sensitivity predicts the development of IGT/T2D over time.
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