Variants and Haplotypes of TCF7L2 Are Associated With β-cell Function in Patients With Newly Diagnosed Type 2 Diabetes: The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 1

J Clin Endocrinol Metab. 2011 Feb;96(2):E389-93. doi: 10.1210/jc.2010-1677. Epub 2010 Dec 15.

Abstract

Context: Intronic variants of TCF7L2 are confirmed genetic risk factors for type 2 diabetes and are associated to alterations in beta cell function in nondiabetic individuals.

Objective: The objective of the study was to test whether TCF7L2 variability may affect β-cell function also in patients with type 2 diabetes.

Design: This was a cross-sectional association study.

Setting: The study was conducted at a university hospital referral center for diabetes.

Patients: Patients included 464 (315 males and 149 females) glutamic acid decarboxylase-negative patients [age: median 59 yr (interquartile range: 52-65); body mass index: 29.3 kg/m(2) (26.5-32.9); fasting plasma glucose: 7.0 mmol/liter (6.1-8.0)] with newly diagnosed type 2 diabetes.

Intervention(s): Interventions included frequently sampled oral glucose tolerance test and euglycemic insulin clamp.

Main outcome measure(s): β-Cell function (derivative control and proportional control); insulin sensitivity; genotypes of the following TCF7L2 single-nucleotide polymorphisms: rs7901695, rs7903146, rs11196205, and rs12255372.

Results: Both rs7901695 and rs7903146 diabetes risk alleles were associated with reduced proportional control of β-cell function (P = 0.019 and P = 0.022, respectively). Two low-frequency haplotypes were associated with extreme (best and worst) phenotypes of β-cell function (P < 0.01). No associations between TCF7L2 genotypes and insulin sensitivity were detected.

Conclusions: TCF7L2 diabetes risk variants, either as single-nucleotide polymorphisms or as haplotypes, detrimentally influence β-cell function and might play a role in determining the metabolic phenotype of patients with newly diagnosed type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Blood Glucose / metabolism
  • Body Mass Index
  • C-Peptide / metabolism
  • Cohort Studies
  • Cross-Sectional Studies
  • Databases, Factual
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Female
  • Genetic Variation
  • Glucose Tolerance Test
  • Haplotypes
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology
  • Insulin-Secreting Cells / physiology*
  • Male
  • Middle Aged
  • Models, Biological
  • Pancreatic Function Tests
  • Polymorphism, Single Nucleotide / genetics
  • Risk Factors
  • Transcription Factor 7-Like 2 Protein / genetics*

Substances

  • Blood Glucose
  • C-Peptide
  • Hypoglycemic Agents
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein