Transcription factor 1 and β‐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, 2ndIR) 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. CONCLUSION: The I27L polymorphism of TCF1 is an independent determinant of beta-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.