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The Common P446L Polymorphism in GCKR Inversely Modulates Fasting Glucose and Triglyceride Levels and Reduces Type 2 Diabetes Risk in the DESIR Prospective General French Population

¹ CNRS 8090–Institute of Biology, Pasteur Institute, Lille, France
² Lille 2 University, Lille, France
³ Regional Institut for Health, Tours, France
⁴ INSERM U695, Paris, France
⁵ René Diderot-Paris 7 University, Paris, France
⁶ Department of Endocrinology–Diabetology and Nutrition, Bichat Claude Bernard Hospital, Paris, France
⁷ INSERM U780-IFR69, Villejuif, France
⁸ University of Paris-Sud, Villejuif, France
⁹ Section of Genomic Medicine, Hammersmith Hospital, Imperial College London, U.K

Corresponding author: Dr. Martine Vaxillaire, martine.vaxillaire{at}good.ibl.fr

OBJECTIVE— Hepatic glucokinase (GCK) is a key regulator of glucose storage and disposal in the liver, where its activity is competitively modulated, with respect to glucose, by binding to glucokinase regulatory protein (GCKR) in the presence of fructose 6-phosphate. Genome-wide association studies for type 2 diabetes identified GCKR as a potential locus for modulating triglyceride levels. We evaluated, in a general French population, the contribution of the GCKR rs1260326-P446L polymorphism to quantitative metabolic parameters and to dyslipidemia and hyperglycemia risk.

RESEARCH DESIGN AND METHODS— Genotype effects of rs1260326 were studied in 4,833 participants from the prospective DESIR (Data from an Epidemiological Study on the Insulin Resistance syndrome) cohort both at inclusion and using the measurements at follow-up.

RESULTS— The minor T-allele of rs1260326 was strongly associated with lower fasting glucose (–1.43% per T-allele; P = 8 x 10^–13) and fasting insulin levels (–4.23%; P = 3 x 10^–7), lower homeostasis model assessment of insulin resistance index (–5.69%; P = 1 x 10^–8), and, conversely, higher triglyceride levels (3.41%; P = 1 x 10^–4) during the 9-year study. These effects relate to a lower risk of hyperglycemia (odds ratio [OR] 0.79 [95% CI 0.70–0.88]; P = 4 x 10^–5) and of incident cases during the study (hazard ratio [HR] 0.83 [0.74–0.95]; P = 0.005). Moreover, an additive effect of GCKR rs1260326(T) and GCK (–30G) alleles conferred lower fasting glycemia (P = 1 x 10^–13), insulinemia (P = 5 x 10^–6), and hyperglycemia risk (P = 1 x 10^–6).

CONCLUSIONS— GCKR-L446 carriers are protected against type 2 diabetes despite higher triglyceride levels and risk of dyslipidemia, which suggests a potential molecular mechanism by which these two components of the metabolic syndrome can be dissociated.

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