BACKGROUND　　Common polymor phisms 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(rs l2255372 and rs7903146) prediet the progression to diabetes in persons with impaired glucose tolerance who were enrolled in the Diabetes Prevention Program，in which lifestyIe intervention or treatment with metformin was compared with placebo.

METHODS　　We genotyped these variants in 3548 participants and performed Cox regression analvses using genotypee，intervention, and their interactions as predictors. We assessed the effect of genotype on measures of insulin secretion and insulin sensitivity at haseline 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 t0 2.01；P<O.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=O.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 obtainted for rs12255372．

CONCLUSIONS　　Common variants in TCF7L2 seem to be associated with an increased risk of diabetes among persons with impaired glucose tolerance．The riskconferring genotypes in TCF7L2 are associated with impaired beta-cell function but not with insulin resistance．

(N Engl J Med 2006；355：24l-50．July 20，2006)