Genetic Polymorphism of Glucokinase on the Risk of Type 2 Diabetes and Impaired Glucose Regulation: Evidence Based on 298, 468 Subjects

Abstract

BackgroundGlucokinase (GCK) is the key glucose phosphorylation enzyme which has attracted considerable attention as a candidate gene for type 2 diabetes (T2D) based on its enzyme function as the first rate-limiting step in the glycolysis pathway and regulates glucose-stimulated insulin secretion. In the past decade, the relationship between GCK and T2D has been reported in various ethnic groups. To derive a more precise estimation of the relationship and the effect of factors that might modify the risk, we performed this meta-analysis.MethodsDatabases including Pubmed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association.ResultsA total of 24 articles involving 88, 229 cases and 210, 239 controls were included. An overall random-effects per-allele OR of 1.06 (95% CI: 1.03–1.09; P<10−4) was found for the GCK −30G>A polymorphism. Significant results were also observed using dominant or recessive genetic models. In the subgroup analyses by ethnicity, significant results were found in Caucasians; whereas no significant associations were found among Asians. In addition, we found that the −30G>A polymorphism is a risk factor associated with increased impaired glucose regulation susceptibility. Besides, −30G>A homozygous was found to be significantly associated with increased fasting plasma glucose level with weighted mean difference (WMD) of 0.15 (95%: 0.05–0.24, P = 0.001) compared with G/G genotype.ConclusionsThis meta-analysis demonstrated that the −30G>A polymorphism of GCK is a risk factor associated with increased T2D susceptibility, but these associations vary in different ethnic populations.

Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

“…GCKR regulates glucokinase, a phosphorylating enzyme that responsible for hepatic glucose metabolism and activates hepatic lipogenesis [108] . Polymorphism of GCKR was found to be significantly associated with increased risk of T2DM, particularly in Asian population [109,110] . Furthermore, polymorphism of GCKR (rs780094 and rs1260326) has been shown to be associated with NAFLD in Chinese people and obese youth respectively [108,111] .…”

“…Given the essential contribution of lipogenesis pathway, another common gene variant, glucokinase regulatory protein (GCKR) gene has been studied extensively [108][109][110] . GCKR regulates glucokinase, a phosphorylating enzyme that responsible for hepatic glucose metabolism and activates hepatic lipogenesis [108] .…”

An interaction effect between glucokinase gene variation and carbohydrate intakes modulates the plasma triglyceride response to a fish oil supplementation

“…Hishida et al (2012) have investigated the impact of gene-diet interaction effect on the risk of dyslipidemia defined as elevated plasma TG and/or low HDL-C concentrations and did not observe interaction effects with GCK gene rs1799884 and the intakes of energy, fat, CHO or alcohol. A recent meta-analysis has shown that the association between rs1799884 and type 2 diabetes varies according to ethnic populations and could be more important among Caucasians than among Asians (Fu et al 2013). In a large-scale gene-centric meta-analysis, the intronic SNP rs2070971 within GCK gene was associated with plasma TG concentrations (Asselbergs et al 2012).…”

“…At high glucose concentrations such as after a meal high in carbohydrates (CHO), fructose-1-phosphate binds with GCKR and releases GCK which enhances glucose metabolism leading to a greater glycolytic flux (Girard et al 1997b;Iynedjian 2009). A few single-nucleotide polymorphisms (SNPs) within GCK have been reported to have an impact on type 2 diabetes risk, glycemia, beta cell function and plasma TG concentrations (Hu et al 2010;Sotos-Prieto et al 2013;Wang et al 2013;Fu et al 2013;Asselbergs et al 2012).…”

Association of TCF7L2 gene polymorphisms with susceptibility to type 2 diabetes mellitus in a Chinese Hui population

“…Although it is well-known that insulin resistance plays a major role in the development of T2DM, the pathogenesis of T2DM is generally considered to result from the interactions between multiple susceptibility genes, as well as from interactions between genes and the environment (Edwards et al, 1997;Fu et al;Li et al, 2013). Transcription factor 7-like 2 (TCF7L2) is a Wnt signaling-associated transcription factor which is expressed in a board range of tissues including the gut and the pancreas.…”