Modulation of Glucokinase Regulatory Protein: A Double-Edged Sword?

Brouwers, Martijn C.G.J.; Jacobs, Chantal; Bast, Aalt; Stehouwer, Coen D. A.; Schaper, Nicolaas C.

doi:10.1016/j.molmed.2015.08.004

Cited by 62 publications

(65 citation statements)

References 97 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One such variant is an intronic SNP, rs780094, which was originally identified to be associated with fasting serum triacyglycerol, insulinemia, and the risk of T2D [8]. As expected for SNPs in high LD, rs780094 and rs1260326 (r 2 = 0.94) overlap in their phenotypical associations [9]. Thus, their independent effects cannot be accurately assessed based on association analysis.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of a FOXA2-regulated transcriptional enhancer at a type 2 diabetes intronic locus that controls GCKR expression in liver cells

et al. 2017

View full text Add to dashboard Cite

BackgroundGenome-wide association studies (GWAS) have identified more than 100 genetic loci associated with type 2 diabetes (T2D). However, the underlying biological mechanisms for many of these associations remain unknown. GWAS signals close to the glucokinase regulatory protein gene (GCKR) have been reported for lipid and glucose metabolism traits and the risk of T2D. We investigated the regulatory function of an intronic locus at GCKR represented by the lead single nucleotide polymorphism (SNP) rs780094.MethodsWe used ENCODE project histone modification and transcription factor binding data to determine the regulatory features of a GCKR intronic locus formed by the high linkage disequilibrium rs780094(C/T), rs780095(G/A), and rs780096(G/C) SNPs. Characterization of the transcriptional activity of this region was assessed by luciferase reporter assays in HepG2 cells and mouse primary hepatocytes. ChIP-qPCR was used to determine the levels of haplotype specific transcription factor binding and histone marks. A CRISPR-dCas9 transcriptional activator system and qPCR were used to activate the locus and measure GCKR expression, respectively. Differential haplotype expression was measured from human liver biopsies.ResultsThe ENCODE data suggest the existence of a liver-specific intragenic enhancer at the locus represented by s780094. We observed that FOXA2 increased the transcriptional activity of this region in a haplotype specific way (CGG > TAC; rs780094, rs780095, and rs780096). In addition, the CGG haplotype showed higher binding to FOXA2 and higher levels of the H3K27Ac histone mark. The epigenetic activation of this locus increased the expression of endogenous GCKR in HepG2 cells, confirming that GCKR is the direct target gene of the enhancer. Finally, we confirmed that the CGG haplotype exhibits higher levels of transcription in human liver.ConclusionsOur results demonstrate the existence of a liver-specific FOXA2-regulated transcriptional enhancer at an intronic T2D locus represented by rs780094, rs780095, and rs780096 SNPs that increases GCKR expression. Differential haplotype regulation suggests the existence of cis regulatory effects that may contribute to the associated traits at this locus.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0453-x) contains supplementary material, which is available to authorized users.

show abstract

Section: Introductionmentioning

confidence: 99%

Identification and characterization of a FOXA2-regulated transcriptional enhancer at a type 2 diabetes intronic locus that controls GCKR expression in liver cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The role of GK in regulating hepatic glucose metabolism is even more complex. In the hepatocyte, GK‐mediated conversion of glucose to glucose‐6‐phosphate (G‐6‐P) increases glycogen formation and, via conversion of glucose to fructose‐6‐phosphate (F‐6‐P), increases lipogenesis . Hepatic GK activity is modulated by an endogenous inhibitor, glucokinase regulatory protein (GKRP), which is localized in the nucleus as an inactive complex with GK at low glucose concentrations, with GK dissociating at high glucose concentrations and translocating to the cytoplasm .…”

mentioning

confidence: 99%

“…Fructose‐1‐phosphate, from dietary fructose, releases GK from GKRP, whereas F‐6‐P prevents dissociation of GK from the complex, leading to feedback inhibition of hepatic GK action. Polymorphisms associated with decreased feedback inhibition of F‐6‐P on GKRP, although increasing hepatic GK function and being associated with reductions in T2D, are associated with increased likelihood of non‐alcoholic fatty liver disease (NAFLD) and hypertriglyceridemia, suggesting the latter as two potential adverse effects of interventions increasing hepatic GK activity . Eventual metabolic fates of G‐6‐P in the hepatocyte include glycolysis, glucose oxidation, glycogen synthesis, and production of glucose, lipids, urea, and urate.…”

mentioning

confidence: 99%

Glucokinase and the potential of glucokinase activation in type 2 diabetes

Bloomgarden

2019

Journal of Diabetes

View full text Add to dashboard Cite

“…This may accelerate the development of nonalcoholic fatty liver disease and hypertriglyceridemia (9). Clinical studies with small-molecule GKRP-glucokinase disruptors are therefore eagerly awaited.…”

mentioning

confidence: 99%

“…We recently reviewed the metabolic effects of such common, functional variants in GCKR and showed that the rs780094 and rs1260326 minor alleles are associated with not only decreased plasma glucose levels but also increased de novo lipogenesis, nonalcoholic fatty liver disease, and plasma triglycerides (9). Notably, many of these studies have been carried out in individuals with normal glucose metabolism.…”

mentioning

confidence: 99%

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

et al. 2016

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Modulation of Glucokinase Regulatory Protein: A Double-Edged Sword?

Cited by 62 publications

References 97 publications

Identification and characterization of a FOXA2-regulated transcriptional enhancer at a type 2 diabetes intronic locus that controls GCKR expression in liver cells

Identification and characterization of a FOXA2-regulated transcriptional enhancer at a type 2 diabetes intronic locus that controls GCKR expression in liver cells

Glucokinase and the potential of glucokinase activation in type 2 diabetes

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

Contact Info

Product

Resources

About