TCF7L2 Polymorphism, Weight Loss and Proinsulin¿Insulin Ratio in the Diabetes Prevention Program by McCaffery Jeanne M, Jablonski Kathleen A, Franks Paul W, Dagogo-Jack Sam, Wing Rena R, Knowler William C, Delahanty Linda, Dabelea Dana, Hamman Richard, Shuldiner Alan R, Florez Jose C, for the Diabetes Prevention Program Research Group in PloS one (2011).

[PMID: 21814547] PubMed


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.

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