Dataset Information

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

ABSTRACT: 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 ?-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 ?-cell function, and hepatic insulin sensitivity predicts the development of IGT/T2D over time.

SUBMITTER: Cropano C

PROVIDER: S-EPMC5521977 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Cropano Catrina C Santoro Nicola N Groop Leif L Dalla Man Chiara C Cobelli Claudio C Galderisi Alfonso A Kursawe Romy R Pierpont Bridget B Goffredo Martina M Caprio Sonia S

Diabetes care 20170613 8

<h4>Objective</h4>In this study, we aimed to explore the mechanism by which <i>TCF7L2</i> rs7903146 risk allele confers susceptibility to impaired glucose tolerance (IGT) or type 2 diabetes (T2D) in obese adolescents.<h4>Research design and methods</h4>The rs7903146 variant in the <i>TCF7L2</i> 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 underwen ...[more]

PMID: 28611053

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Project description:BackgroundThyrotropin (TSH) levels display a positive association with body mass index (BMI), and the prevalence of isolated hyperthyrotropinemia is higher in obese adolescents compared to their normal weight controls. However, the metabolic significance of the higher TSH in obese adolescents is less clear. The objective of this study was to determine the relationship between TSH concentrations and insulin sensitivity, lipids, and adipokines in euthyroid, non-diabetic, obese adolescents.MethodsThirty-six euthyroid, non-diabetic, obese adolescents between the ages of 12 and 18 years underwent a 75 g oral glucose tolerance test. Insulin sensitivity (Si) and pancreatic β-cell function as assessed by disposition index (DI) were measured using the oral glucose minimal model approach. Cholesterol (total, low-density lipoprotein [LDL-C], and high-density lipoprotein [HDL-C]), triglycerides (TG), interleukin-6 (IL-6), total and high molecular weight (HMW) adiponectin, and retinol binding protein-4 (RBP4) were also determined. Associations between measures of thyroid function and Si, DI, lipids, and adipokines were computed using Pearson's correlation coefficient and multiple regression analysis.ResultsThe mean age of the subjects was 14.3±1.88 years, and the mean BMI was 32.5±4.65 kg/m2; 97% were non-Hispanic white and 47% were male. The mean TSH was 2.7±1.2 mIU/L. Increasing serum TSH was correlated with decreasing Si (log Si) in the entire cohort (p=0.03), but this relationship persisted only in males (p=0.02). The correlation between TSH and Si in males remained significant after adjusting for BMI (p=0.02). There was no correlation between TSH and pancreatic β-cell function as assessed by DI (p=0.48). TSH correlated positively with LDL-C (p=0.04) and IL-6 (p=0.03), but these associations vanished or weakened after adjusting for BMI (LDL-C p-value=0.44; IL-6 p-value=0.07).ConclusionsThis study suggests a sex-specific association between TSH and insulin sensitivity in euthyroid, non-diabetic, obese adolescent males. Prospective studies are warranted to explore further this sexual dimorphism in the relationship between thyroid function and insulin sensitivity and to determine if obese adolescents with insulin resistance receiving thyroid supplements for hypothyroidism would benefit from targeting TSH levels in the lower half of normal range.

Dataset Information

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

Publications

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

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