The results of this study indicate that the variation in the TCF7L2
gene previously associated with T2D and BMI does not predict ability to lose weight. This effect was consistent across those randomized to the intensive lifestyle, metformin treatment, or placebo interventions, indicating that the extent and mode of weight loss do not influence the genetic associations. However, the T allele at rs7903146 was associated with higher proinsulin
insulin ratio at baseline and, once baseline values were statistically adjusted for, change in the proinsulin
insulin ratio over a median of 2.5 year follow-up. This effect was consistent across treatment arms in DPP despite significant weight losses in the lifestyle and metformin groups, relative to the placebo group.
As new genetic associations with T2D continue to emerge, it is plausible that genetic information may be used to guide the choice of preventive interventions. Before this can be achieved, it will be important to document the potential impact of these diabetes risk loci on the effectiveness of both pharmacological and behavioral interventions. For example, the extent of weight loss in response to a standardized caloric restriction regimen is highly heritable in twin studies 
. Genetic loci previously associated with T2D or obesity serve as leading candidates that may promote resistance to weight loss in response to a behavioral intervention. In the current paper, we find that the diabetes risk marker rs7903146 in TCF7L2
does not impact the ability to lose weight in response to metformin or behavioral intervention. This is consistent with one prior paper reporting no association of rs7903146 with the extent of weight loss in response to a short-term hypocaloric diet 
. However, were unable to replicate a second paper from the Tuebingen Lifestyle Intervention Program (TULIP) reporting that carriers of the T allele showed blunted weight loss in response to a nine-month combined diet and exercise program 
. Of relevance to this report, we found no heterogeneity of effect across treatment arms, indicating that the effect of genotype did not differ in the lifestyle intervention arm, relative to the metformin or placebo arms. We also found no heterogeneity by time, indicating that genotype effects at year 1 did not differ significantly from other time points. Several potential differences across the studies may account for the different results, including length of follow-up, nature or intensity of the lifestyle intervention and the extent of weight loss achieved. Of note, the TULIP included a dietary fiber intervention not included in the DPP. Taken together with a recent report indicating that dietary fiber may alter the association between TCF7L2
and diabetes 
, it remains possible that changing certain components of the diet, such as fiber intake, may alter risks associated with TCF7L2
This paper also extends prior results examining the impact of this locus on proinsulin
insulin ratio. A greater proinsulin
insulin ratio is thought to reflect a deficit in β-cell secretory function and TCF7L2
appears to play a critical role in β-cell survival and glucose-stimulated insulin secretion 
. Greater proinsulin
insulin ratios have consistently been shown among T allele carriers at rs7903146 but associations with proinsulin level have been less consistent 
. In the present study, we found that rs7903146 is associated with a lower insulin level and, as a result, an elevated proinsulin
insulin ratio at baseline. Further, the elevated proinsulin
insulin ratio persisted over 2.5 years of follow-up once baseline values were statistically controlled for and was consistent across treatment arms. Thus, the impact of genotype on the proinsulin
insulin ratio does not appear to be altered by metformin or lifestyle intervention. Proinsulin
insulin ratio decreased in the metformin and lifestyle intervention arms in line with the expected improvement in proinsulin
insulin ratio with increased insulin sensitivity. However, the persistence of differences in proinsulin
insulin ratios across genotypic groups at TCF7L2
rs7903146, despite interventions shown to significantly improve insulin sensitivity 
, raises the possibility that this defect may be caused by a specific effect of TCF7L2
on proinsulin processing, β-cell proliferation and/or differentiation, or insulin vesicle trafficking, rather than by the general stress brought on the β cell by increased insulin demand.
Helgason and colleagues 
reported that a haplotype including the C allele at rs7903146 and the A allele at rs10885406 (HapA) was positively associated with BMI, whereas the absence of HapA (noted as HapB) including the diabetes risk T allele at rs7903146 was negatively associated with BMI. We found the associations of HapA with weight and proinsulin
insulin ratio to largely be driven by variation in the component SNP, rs7903146.
Taken together, the combination of a lack of impact of TCF7L2
genotypes on the ability to lose weight in this study, but its consistent impact on the proinsulin
insulin ratio, suggests that persons who carry high-risk genotypes at this locus can successfully lose weight to counter diabetes risk, despite consistent deficits in proinsulin processing.