Transcription Factor 1 and Beta-Cell Function in Glucose-Tolerant Subjects

Aims Although beta-cell dysfunction and insulin resistance are observed in patients with Type 2 diabetes, beta-cell dysfunction plays a crucial role in the development of the disease. Mutations of transcription factor 1 (TCF1, or hepatocyte nuclear factor-1alpha) affect beta-cell function. We examined the impact of amino acid polymorphisms of this gene on beta- cell function in 60 glucose-tolerant Caucasians . Methods Insulin sensitivity index (ISI) and 1st and 2nd phase insulin responses (1stIR, 2 ndIR) were measured using the hyperglycaemic clamp. The genotypes were determined from genomic DNA and their impact on beta-cell function was investigated. Results Among three polymorphisms (I27L, A98V, and S487N), significant impact on beta-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. Conclusions The I27L polymorphism of TCF1 is an independent determinant of beta-cell function by affecting both 1st and 2 nd 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