Triglyceride response to an intensive lifestyle intervention is enhanced in carriers of the GCKR Pro446Leu polymorphism.

Academic Article


  • CONTEXT: 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). INTERVENTIONS AND MAIN OUTCOME MEASURES: 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


  • Adaptor Proteins, Signal Transducing, Alleles, Blood Glucose, C-Reactive Protein, Diabetes Mellitus, Type 2, Disease Progression, Female, Genetic Predisposition to Disease, Genotype, Heterozygote, Humans, Insulin Resistance, Life Style, Male, Polymorphism, Single Nucleotide, Triglycerides
  • Digital Object Identifier (doi)

    Author List

  • Pollin TI; Jablonski KA; McAteer JB; Saxena R; Kathiresan S; Kahn SE; Goldberg RB; Altshuler D; Florez JC; Diabetes Prevention Program Research Group
  • Start Page

  • E1142
  • End Page

  • E1147
  • Volume

  • 96
  • Issue

  • 7