A Common Gene Variant in Glucokinase Regulatory Protein Interacts With Glucose Metabolism on Diabetic Dyslipidemia: the Combined CODAM and Hoorn Studies

Abstract

OBJECTIVESmall molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP) are potential new glucose-lowering targets. They stimulate hepatic glucose disposal by increasing glucokinase activity in the liver. It can, however, be anticipated that increased hepatic glucokinase activity might be accompanied by the development of hypertriglyceridemia, particularly in type 2 diabetes. We examined whether the strength of association between rs1260326, a common, functional gene variant in GKRP, and plasma lipids is affected by glucose metabolism. RESEARCH DESIGN AND METHODSrs1260326 was genotyped in subjects with normal glucose metabolism (n = 497), subjects with impaired glucose metabolism (n = 256), and patients with type 2 diabetes (n = 351) in the combined Hoorn and Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) studies. RESULTSThe strength of association between the rs1260326 minor T allele and plasma triglycerides increased from normal glucose metabolism to impaired glucose metabolism to type 2 diabetes (P for interaction = 0.002). The inverse relation between rs1260326 and plasma HDL cholesterol was again most prominent in type 2 diabetes (P for interaction = 0.004). Similar trends were observed when the Hoorn and CODAM cohorts were analyzed separately. Comparable results were obtained when glucose metabolism strata were replaced by continuous indices of glucose metabolism, i.e., HbA 1c and fasting plasma glucose. CONCLUSIONSThese findings illustrate that common gene variants, such as rs1260326, can have substantial effect sizes when they are studied in specific populations, such as type 2 diabetes. Moreover, our results shed light on potential side effects of small molecule disruptors of the GKRP-glucokinase complex, especially when glucose control is suboptimal.

Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality

“…3a), it can be predicted that it will indeed result in increased de novo lipogenesis and NAFLD, as well as dyslipidaemia and CVD [51,52]. Of interest, we and others have shown that the effects of this common GCKR variant on hepatic fat accumulation and plasma triacylglycerols are more pronounced in conditions of obesity and hyperglycaemia [62,63]. This would imply that obese individuals and those with poorly controlled type 2 diabetes are more prone to the undesired side effects of liver-specific glucokinase activators.…”

Association of common gene variants in glucokinase regulatory protein with cardiorenal disease: A systematic review and meta-analysis

“…Furthermore, a synergistic effect between GCKR and type 2 diabetes on CAD risk cannot be ruled out. We previously demonstrated that the effects of the GCKR effect allele on plasma lipid levels were more pronounced in patients with type 2 diabetes when compared to healthy individuals [ 52 ]. A similar interaction between GCKR and type 2 diabetes on CAD risk would seriously decrease the applicability of small molecule disruptors of the glucokinase-GKRP complex as new antidiabetic drug.…”

The endothelial function biomarker soluble E‐selectin is associated with nonalcoholic fatty liver disease

“…The Hoorn and CODAM studies were performed according to the Declaration of Helsinki and approved by the local Medical Ethical Committees. As the protocols of both studies were similar, data were combined for statistical analyses, as has been done before …”

“…Genotyping of GCKR (rs1260326) and PNPLA3 (rs738409) was performed with validated Invitrogen TaqMan assays (Thermo Fisher Scientific). In CODAM, GCKR (rs1260326) was genotyped as part of a genome‐wide association study array, using a HumanOmniExpress BeadChip (Illumina) . Genotyping of rs1260326 and rs738409 was successful in 1265 individuals.…”