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Aims    TCF7L2  variants have been associated with type 2 diabetes, body mass index (BMI), and deficits in proinsulin processing and insulin secretion. Here we sought to test whether these effects were apparent in high-risk individuals and modify treatment responses.    Methods  We examined the potential role of the  TCF7L2  rs7903146 variant in predicting resistance to weight loss or a lack of improvement of proinsulin processing during 2.5-years of follow-up participants (N = 2,994) from the Diabetes Prevention Program (DPP), a randomized controlled trial designed to prevent or delay diabetes in high-risk adults.    Results  We observed no difference in the degree of weight loss by rs7903146 genotypes. However, the T allele (conferring higher risk of diabetes) at rs7903146 was associated with higher fasting proinsulin at baseline ( P <0.001), higher baseline proinsulin∶insulin ratio (p<0.0001) and increased proinsulin∶insulin ratio over a median of 2.5 years of follow-up ( P  = 0.003). Effects were comparable across treatment arms.    Conclusions  The combination of a lack of impact of the  TCF7L2  genotypes on the ability to lose weight, but the presence of a consistent effect on the proinsulin∶insulin ratio over the course of DPP, suggests that high-risk genotype carriers at this locus can successfully lose weight to counter diabetes risk despite persistent deficits in insulin production.

TCF7L2 Polymorphism, Weight Loss and Proinsulin∶Insulin Ratio in the Diabetes Prevention Program