TCF 7 L 2 Polymorphism , Weight Loss and Proinsulin : Insulin Ratio in the Diabetes Prevention Program

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. Citation: McCaffery JM, Jablonski KA, Franks PW, Dagogo-Jack S, Wing RR, et al. (2011) TCF7L2 Polymorphism, Weight Loss and Proinsulin:Insulin Ratio in the Diabetes Prevention Program. PLoS ONE 6(7): e21518. doi:10.1371/journal.pone. 0021518 Editor: Jose A. L. Calbet, University of Las Palmas de Gran Canaria, Spain Received January 11, 2011; Accepted June 2, 2011; Published July 26, 2011 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study; collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and Prevention, and the American Diabetes Association. This research was also supported, in part, by the intramural research program of the NIDDK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Bristol-Myers Squibb and Parke-Davis provided medication; LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co. and Quaker Oats Co. donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: dppmail@bsc.gwu. edu " A complete list of centers, investigators, and staff can be found in Text S1. PLoS ONE | www.plosone. org 1 July 2011 | Volume 6 | Issue 7 | e21518