Transcription factor 1 and β-cell function in glucose-tolerant subjects
Journal
Diabetic Medicine
Journal Volume
20
Journal Issue
3
Pages
225-230
Date Issued
2003
Author(s)
Abstract
Aims: Although β-cell dysfunction and insulin resistance are observed in patients with Type 2 diabetes, β-cell dysfunction plays a crucial role in the development of the disease. Mutations of transcription factor 1 (TCF1, or hepatocyte nuclear factor-1α) affect β-cell function. We examined the impact of amino acid polymorphisms of this gene on β-cell function in 60 glucose-tolerant Caucasians. Methods: Insulin sensitivity index (ISI) and 1st and 2nd phase insulin responses (1stIR, 2ndIR) were measured using the hyperglycaemic clamp. The genotypes were determined from genomic DNA and their impact on β-cell function was investigated. Results: Among three polymorphisms (I27L, A98V, and S487N), significant impact on β-cell function was found in the I27L polymorphism. Univariate analyses revealed differences for the I27L polymorphism in both 1stir (P = 0.0052) and 2ndIR (P = 0.0432). Multivariate analysis revealed that the I27L polymorphism (P = 0.0124) with ISI accounted for 32% of the variation in 1stIR and had a marginal impact on 2ndIR (P = 0.0343), accounting for 52% of the variation with ISI and age. By dissecting out the impact of other covariate(s), the I27L polymorphism independently explained 12% of the variation in 1stIR and 6% of the variation in 2ndIR. Conclusion: The I27L polymorphism of TCF1 is an independent determinant of β-cell function by affecting both 1st and 2nd phase insulin response. This polymorphism could play a role in the pathogenesis of Type 2 diabetes. A large-scale association study (approx. 2000 subjects) will be required to demonstrate the genetic susceptibility of this polymorphism to Type 2 diabetes.
SDGs
Other Subjects
adult; amino acid sequence; article; Caucasian; cell function; controlled study; DNA polymorphism; female; gene mutation; genetic susceptibility; glucose tolerance; human; insulin resistance; insulin sensitivity; major clinical study; male; multivariate analysis; non insulin dependent diabetes mellitus; pancreas islet beta cell; pathogenesis; protein function; Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Hepatocyte Nuclear Factor 1-alpha; Humans; Insulin Infusion Systems; Insulin Resistance; Insulin-Secreting Cells; Male; Polymorphism, Genetic
Type
journal article