TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program

Abstract

Background: Common polymorphisms of the transcription factor 7-like 2 gene (TCF7L2) have recently been associated with type 2 diabetes. We examined whether the two most strongly associated variants (rs12255372 and rs7903146) predict the progression to diabetes in persons with impaired glucose tolerance who were enrolled in the Diabetes Prevention Program, in which lifestyle intervention or treatment with metformin was compared with placebo.

Methods: We genotyped these variants in 3548 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors. We assessed the effect of genotype on measures of insulin secretion and insulin sensitivity at baseline and at one year.

Results: Over an average period of three years, participants with the risk-conferring TT genotype at rs7903146 were more likely to have progression from impaired glucose tolerance to diabetes than were CC homozygotes (hazard ratio, 1.55; 95 percent confidence interval, 1.20 to 2.01; P<0.001). The effect of genotype was stronger in the placebo group (hazard ratio, 1.81; 95 percent confidence interval, 1.21 to 2.70; P=0.004) than in the metformin and lifestyle-intervention groups (hazard ratios, 1.62 and 1.15, respectively; P for the interaction between genotype and intervention not significant). The TT genotype was associated with decreased insulin secretion but not increased insulin resistance at baseline. Similar results were obtained for rs12255372.

Conclusions: Common variants in TCF7L2 seem to be associated with an increased risk of diabetes among persons with impaired glucose tolerance. The risk-conferring genotypes in TCF7L2 are associated with impaired beta-cell function but not with insulin resistance. (ClinicalTrials.gov number, NCT00004992. [ClinicalTrials.gov]).

Figure 1. Incidence of Diabetes According to Treatment Group and Genotype at Variant rs7903146

The P values were determined by the log-rank test.

Figure 2. Effects of Genotype at rs7903146 on Insulin Secretion at Baseline as Measured by the Mean (±SE) Insulin:Glucose Ratio (Panel A) and the Corrected Insulin Response (Panel B)

To convert the insulin:glucose ratio to picomoles per liter ÷ millimoles per liter, multiply by 125.1; to convert the corrected insulin response to picomoles per liter ÷ (millimoles per liter)², multiply by 2254.9. Statistical comparisons were made on log-transformed values where appropriate. All pairwise comparisons are significant at a P value of less than 0.02; in comparisons between the CC and TT genotypes, the P value is less than 0.001 for both measures of insulin secretion. Although baseline glucose concentrations did not differ significantly across genotypic groups at 0 and 30 minutes, TT homozygotes had significantly lower insulin concentrations at both time points — at 30 minutes, CC, CT, and TT participants had mean insulin concentrations (±SD) of 106.0±69.7, 96.0±56.1, and 89.1±57.2 μU per milliliter, respectively (P<0.001). To convert microunits per milliliter to picomoles per liter, multiply by 6.94.

Figure 3. Insulin Secretion and Insulin Sensitivity at Baseline for Each Genotype at rs7903146

Composite beta-cell function is estimated by the relationship between insulin secretion (the insulin:glucose ratio and the corrected insulin response) and insulin sensitivity (insulin-sensitivity index and 1 ÷ fasting insulin). The curves represent the regression line of the logarithm of estimated insulin secretion as a linear function of the logarithm of estimated insulin sensitivity for all participants at baseline, distributed according to genotype at rs7903146. The mean for each group is indicated by the point estimate in each curve. Carriers of the T allele have decreased insulin secretion accompanied by an increase in insulin sensitivity. The shift of the curve downward and to the left in TT homozygotes suggests a defect in composite beta-cell function. To convert insulin-sensitivity index and 1 ÷ fasting insulin to (picomoles per liter × millimoles per liter)⁻¹, multiply by 0.144.