title: TCF7L2 polymorphism, weight loss and proinsulin:insulin ratio in the diabetes prevention program.
abstract: OBJECTIVE
  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.
authors.affiliation: The Biostatistics Center, The George Washington University, Rockville, Maryland, United States of America. dppmail@bsc.gwu.edu
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: McCaffery
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Jablonski
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
authors.forename: Sam
authors.initials: S
authors.lastname: Dagogo-Jack
authors.forename: Rena R
authors.initials: RR
authors.lastname: Wing
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.forename: Linda
authors.initials: L
authors.lastname: Delahanty
authors.forename: Dana
authors.initials: D
authors.lastname: Dabelea
authors.forename: Richard
authors.initials: R
authors.lastname: Hamman
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
mesh_terms: D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics* / Q000517:prevention & control*; D005215:Fasting; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011384:Proinsulin / Q000235:genetics* / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*; D015431:Weight Loss / Q000235:genetics*
chemical_list: D007328:Insulin; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D011384:Proinsulin