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

Abstract

,9 for the DESIR Study Group 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 (Ϫ1.43% per T-allele; P ϭ 8 ϫ 10 Ϫ13 ) and fasting insulin levels (Ϫ4.23%; P ϭ 3 ϫ 10 Ϫ7 ), lower homeostasis model assessment of insulin resistance index (Ϫ5.69%; P ϭ 1 ϫ 10 Ϫ8 ), and, conversely, higher triglyceride levels (3.41%; P ϭ 1 ϫ 10 Ϫ4 ) 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 ϭ 4 ϫ 10 Ϫ5 ) and of incident cases during the study (hazard ratio ; P ϭ 0.005). Moreover, an additive effect of GCKR rs1260326(T) and GCK (Ϫ30G) alleles conferred lower fasting glycemia (P ϭ 1 ϫ 10 Ϫ13 ), insulinemia (P ϭ 5 ϫ 10 Ϫ6 ), and hyperglycemia risk (P ϭ 1 ϫ 10 Ϫ6 ). CONCLUSIONS-GCKR-L446carriers 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.

Association of the GCKR rs780094 polymorphism with metabolic traits including carotid intima-media thickness in Japanese community-dwelling men, but not in women

“…It has been recently shown that novel single nucleotide polymorphisms (SNPs) of rs780094 in the GCKR are candidate susceptibility variants in association with type 2 diabetes mellitus (T2DM) [7]. This SNP, rs780094, is located at intron 16 and has been shown to have strong linkage disequilibrium (r 2 = 0.932) with another SNP, rs1260326 (a non-synonymous SNP, Pro446Leu).…”

Common variants at the GCK, GCKR, G6PC2–ABCB11 and MTNR1B loci are associated with fasting glucose in two Asian populations

“…It has been reported that genetic effects explain 54.8% of the variance of glucose levels in a European population [4]. Recent progress in complex-trait genetics has allowed the identification of loci regulating FPG levels [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”

“…Several loci influencing FPG levels have been identified or verified by genome-wide association (GWA) studies of Europeans; these include glucokinase (GCK) [5][6][7], glucokinase regulatory protein (GCKR) [8][9][10]13], glucose-6-phosphatase catalytic subunit 2 (G6PC2), the ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11) [14][15][16][17], and melatonin receptor 1B (MTNR1B) [16][17][18].…”

Discrete associations of the GCKR variant with metabolic risk in a Chinese population: longitudinal change analysis

“…This discrete association with lipid and glucose metabolism has been replicated in several studies [4][5][6][7][8][9]; notably, these previous studies were performed in cross-sectional settings, mainly in white populations. Studies assessing the association of GCKR variants with incident type 2 diabetes and dyslipidaemia in prospective cohorts are sparse [8], especially those focusing on the longitudinal changes in metabolic traits, or in other ethnic groups [9].…”

“…Intriguingly, several recent genome-wide association studies (GWASs) have shown that variants in glucokinase regulatory protein (GRP) gene (GCKR) were related to elevated blood TG, total cholesterol (TC) and lipoprotein levels, but showed significant associations with lower glucose levels and a reduced risk of type 2 diabetes [1][2][3]. This discrete association with lipid and glucose metabolism has been replicated in several studies [4][5][6][7][8][9]; notably, these previous studies were performed in cross-sectional settings, mainly in white populations. Studies assessing the association of GCKR variants with incident type 2 diabetes and dyslipidaemia in prospective cohorts are sparse [8], especially those focusing on the longitudinal changes in metabolic traits, or in other ethnic groups [9].…”