| Triglyceride response to an intensive lifestyle intervention is enhanced in carriers of the GCKR Pro446Leu polymorphism. | |
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MedLine Citation:
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PMID: 21525158 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Toni I Pollin; Kathleen A Jablonski; Jarred B McAteer; Richa Saxena; Sekar Kathiresan; Steven E Kahn; Ronald B Goldberg; David Altshuler; Jose C Florez; |
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Publication Detail:
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Type: Clinical Trial; Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2011-04-27 |
Journal Detail:
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Title: The Journal of clinical endocrinology and metabolism Volume: 96 ISSN: 1945-7197 ISO Abbreviation: J. Clin. Endocrinol. Metab. Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-07-07 Completed Date: 2011-09-12 Revised Date: 2012-04-16 |
Medline Journal Info:
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Nlm Unique ID: 0375362 Medline TA: J Clin Endocrinol Metab Country: United States |
Other Details:
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Languages: eng Pagination: E1142-7 Citation Subset: AIM; IM |
Affiliation:
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Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland21201, USA. dppmail@bsc.gwu.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing
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genetics*,
metabolism Alleles Blood Glucose / genetics C-Reactive Protein / metabolism Diabetes Mellitus, Type 2 / genetics*, metabolism, prevention & control Disease Progression Female Genetic Predisposition to Disease Genotype Heterozygote Humans Insulin Resistance / genetics Life Style* Male Polymorphism, Single Nucleotide Triglycerides / blood |
| Grant Support | |
ID/Acronym/Agency:
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R01 DK072041/DK/NIDDK NIH HHS; R01 DK072041-08/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adaptor Proteins, Signal Transducing; 0/Blood Glucose; 0/GCKR protein, human; 0/Triglycerides; 9007-41-4/C-Reactive Protein |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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