title: Triglyceride response to an intensive lifestyle intervention is enhanced in carriers of the GCKR Pro446Leu polymorphism.
abstract: BACKGROUND
  Glucokinase regulatory protein (GCKR) regulates the trafficking and enzymatic activity of hepatic glucokinase, the rate-limiting enzyme in glycogen synthesis and glycolysis. The intronic single-nucleotide polymorphism (SNP) rs780094 (intron 16) and the missense SNP rs1260326 (P446L) in the GCKR gene are strongly associated with increased circulating triglyceride and C-reactive protein levels and, paradoxically, reductions in diabetes incidence, fasting glucose levels, and insulin resistance. OBJECTIVE, SETTING, AND PATIENTS: We sought to replicate these associations and evaluate interactions with lifestyle and metformin interventions in the multiethnic Diabetes Prevention Program (DPP).
  
  
  METHODS
  We genotyped the two GCKR SNP in 3346 DPP participants and evaluated association with progression to diabetes and both baseline levels and changes in triglycerides, homeostasis model assessment of insulin resistance (HOMA-IR), oral disposition index, and inflammatory markers along with their interactions with DPP interventions.
  
  
  RESULTS
  GCKR variation did not predict development of type 2 diabetes. At baseline, the 446L allele was associated with higher triglyceride and C-reactive protein levels (both P < 0.0001) and lower fasting glucose (P = 0.001) and HOMA-IR (P = 0.06). The lifestyle intervention was associated with a decrease in magnitude of the effect of the 446L allele on triglyceride levels (interaction P = 0.04). Metformin was more effective in reducing HOMA-IR in carriers of the P446 allele (interaction P = 0.05).
  
  
  CONCLUSIONS
  Intensive lifestyle intervention appears to partially mitigate the effect of the 446L allele on higher triglycerides, whereas the P446 allele appears to enhance responsiveness to the HOMA-IR-lowering effect of metformin.
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland21201, USA. dppmail@bsc.gwu.edu
authors.forename: Toni I
authors.initials: TI
authors.lastname: Pollin
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Jablonski
authors.forename: Jarred B
authors.initials: JB
authors.lastname: McAteer
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kahn
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Goldberg
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D001786:Blood Glucose / Q000235:genetics; D002097:C-Reactive Protein / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008019:Life Style; D008297:Male; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; C485100:GCKR protein, human; D014280:Triglycerides; D002097:C-Reactive Protein