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

• Published in: The journal of clinical endocrinology and metabolism 2011-02, Vol.96 (2), p.E389-E393
• Main Authors: Bonetti, S, Trombetta, M, Malerba, G, Boselli, L, Trabetti, E, Muggeo, M, Stoico, V, Negri, C, Pignatti, P. F, Bonora, E, Bonadonna, R. C
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2010-1677

TCF7L2 variants influence β-cell function and may play a role in determining the metabolic phenotype of patients with newly diagnosed type 2 diabetes mellitus. 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/m2 (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.