title: 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.
abstract: BACKGROUND
  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.
  
  
  METHODS
  This was a cross-sectional association study.
  
  
  METHODS
  The study was conducted at a university hospital referral center for diabetes.
  
  
  METHODS
  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.
  
  
  METHODS
  Interventions included frequently sampled oral glucose tolerance test and euglycemic insulin clamp.
  
  
  METHODS
  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.
authors.affiliation: Department of Medicine, University of Verona, Verona, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bonetti
authors.forename: M
authors.initials: M
authors.lastname: Trombetta
authors.forename: G
authors.initials: G
authors.lastname: Malerba
authors.forename: L
authors.initials: L
authors.lastname: Boselli
authors.forename: E
authors.initials: E
authors.lastname: Trabetti
authors.forename: M
authors.initials: M
authors.lastname: Muggeo
authors.forename: V
authors.initials: V
authors.lastname: Stoico
authors.forename: C
authors.initials: C
authors.lastname: Negri
authors.forename: P F
authors.initials: PF
authors.lastname: Pignatti
authors.forename: E
authors.initials: E
authors.lastname: Bonora
authors.forename: R C
authors.initials: RC
authors.lastname: Bonadonna
mesh_terms: D000368:Aged; D000483:Alleles; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002096:C-Peptide / Q000378:metabolism; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D016208:Databases, Factual; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D014644:Genetic Variation; D005951:Glucose Tolerance Test; D006239:Haplotypes; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010186:Pancreatic Function Tests; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007004:Hypoglycemic Agents; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein