Affinage

GCKR

Glucokinase regulatory protein · UniProt Q14397

Length
625 aa
Mass
68.7 kDa
Annotated
2026-06-10
89 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

The GCKR symbol resolves to two functionally distinct proteins in this corpus, and the timeline coheres around the better-characterized one: the glucokinase regulatory protein (GKRP), a hepatic regulator of glucose metabolism (PMID:8589523, PMID:19643913). GKRP binds and stabilizes hepatic glucokinase (GCK), sequestering it in the nucleus in a fructose-6-phosphate (F6P)-dependent manner; loss of GCKR reduces hepatic GCK protein and activity (PMID:22038520, PMID:23573289). The common P446L variant (rs1260326) shows attenuated response to physiologically relevant F6P, indirectly raising GCK activity, while leaving F1P regulation and dose-dependent inhibition intact (PMID:19643913). P446L-GKRP also displays reduced protein expressivity, decreased nuclear localization, weaker direct GCK interaction by FRET, and diminished nuclear GCK sequestration (PMID:22038520, PMID:37031802). Functionally, the variant shifts metabolic flux toward glycolysis and hepatic de novo lipogenesis: rs1260326 risk-genotype carriers show higher fasting hepatic de novo lipogenesis and glucose oxidation (PMID:26043229), P446L knockin mice show lower blood glucose with altered hepatic cholesterol homeostasis (PMID:37031802), and rare deleterious variants associate with hypertriglyceridemia and drive ectopic fat deposition in transgenic zebrafish (PMID:24879641, PMID:31369557). GCKR expression is itself controlled by a liver-specific FOXA2-regulated intragenic enhancer, and is inducible by glucagon (PMID:28683826, PMID:30375486). This metabolic role frames GKRP as a determinant of glucokinase-activator drug efficacy and hepatic lipid response (PMID:39173844). Separately and incoherently with the GKRP findings, a set of discoveries describe a germinal-center kinase-related serine/threonine kinase (also called GCKR) that is activated downstream of Bcr-Abl/Ras and TNF/TRAF2/Ubc13 to stimulate the SAPK/JNK pathway and modulates Wnt signaling via GSK3β (PMID:9949177, PMID:12591926, PMID:16914735); these likely reflect a separate protein sharing the symbol.

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1995 High

    Establishing the human GCKR sequence, size, and chromosomal location provided the molecular foundation for studying the glucokinase regulatory protein in humans.

    Evidence cDNA cloning from HepG2 cells with FISH and somatic cell hybrid mapping

    PMID:8589523

    Open questions at the time
    • Did not establish function biochemically
    • No variant or disease link defined
  2. 1998 High

    Defining the gene's exon-intron structure and identifying the common exon-15 P446L polymorphism set up the central variant studied thereafter.

    Evidence Genomic clone characterization, RT-PCR/RACE, RNase protection, SSCP screening

    PMID:9570959

    Open questions at the time
    • Functional consequence of P446L not yet tested
    • No phenotypic association established
  3. 1999 Medium

    A distinct GCKR-named serine/threonine kinase was shown to act downstream of Bcr-Abl via Ras to drive SAPK activation, opening a kinase-signaling thread that is mechanistically unrelated to the hepatic GKRP findings.

    Evidence Co-IP, kinase assays, dominant-negative expression in CML cell lines

    PMID:9949177

    Open questions at the time
    • Relationship to the hepatic GKRP protein not reconciled (likely a symbol collision)
    • No structural basis for kinase activation defined
  4. 2003 Medium

    The kinase thread was extended to TNF signaling, showing TRAF2 and Ubc13/Uev1A-mediated K63 ubiquitination drive kinase oligomerization and SAPK activation.

    Evidence siRNA/dominant-negative, Co-IP, kinase assays in HEK293T

    PMID:12591926

    Open questions at the time
    • Single-lab signaling model
    • No reconciliation with the metabolic GKRP role
  5. 2006 Medium

    The kinase was linked to Wnt signaling in B lymphocytes through GSK3β interaction, further developing a signaling role separate from glucose metabolism.

    Evidence siRNA knockdown, Co-IP, pathway readouts in B cells

    PMID:16914735

    Open questions at the time
    • Single-lab finding
    • Mechanistic overlap with hepatic GKRP unresolved
  6. 2009 High

    Reconstitution showed P446L-GKRP responds poorly to physiological F6P, explaining how the variant indirectly raises glucokinase activity without altering F1P regulation.

    Evidence In vitro kinetic assays with recombinant WT and P446L GKRP plus GCK

    PMID:19643913

    Open questions at the time
    • Cellular and in vivo consequences not yet shown
    • Did not address nuclear sequestration
  7. 2011 High

    Cell-biological work resolved the mechanism: P446L reduces nuclear localization, weakens direct GCK binding by FRET, and impairs nuclear GCK sequestration.

    Evidence Quantitative nuclear fluorescence and sensitized-emission FRET in HeLa and primary hepatocytes

    PMID:22038520

    Open questions at the time
    • In vivo metabolic flux consequence not measured here
    • Effect on downstream lipogenesis not tested
  8. 2013 Medium

    Comparative genomics established that GKRP stabilizes hepatic GCK protein, with GCKR loss tracking hepatic glucokinase deficiency across vertebrates.

    Evidence Cross-species sequence analysis correlated with published hepatic GCK activity

    PMID:23573289

    Open questions at the time
    • No direct biochemical reconstitution of stabilization
    • Correlative rather than mechanistic
  9. 2014 Medium

    Functional screening of 18 rare variants linked deleterious GCKR alleles to hypertriglyceridemia at the population level while showing poor within-family co-segregation.

    Evidence High-throughput variant biochemistry plus family segregation analysis

    PMID:24879641

    Open questions at the time
    • Low individual predictive value
    • Tissue-level flux mechanism not directly measured
  10. 2015 Medium

    Human isotope tracing tied the rs1260326 risk genotype directly to elevated hepatic de novo lipogenesis and glucose oxidation, linking the variant to lipid synthesis flux.

    Evidence Deuterium incorporation into VLDL-palmitate in obese adolescents (n=14)

    PMID:26043229

    Open questions at the time
    • Small sample
    • Direct causal chain from GKRP to DNL not isolated in vivo
  11. 2017 High

    A FOXA2-regulated intragenic enhancer was shown to control GCKR transcription in an allele-specific manner, adding a regulatory layer to locus function.

    Evidence Reporter assays, ChIP-qPCR, CRISPR-dCas9 activation, allele-specific expression in human liver

    PMID:28683826

    Open questions at the time
    • Interaction with coding P446L effect not jointly modeled
    • Physiological haplotype consequences not measured
  12. 2017 Low

    Genetic association linked the Leu446 variant to circulating FGF21, with a proposed GCK–malonyl-CoA–ChREBP mechanism.

    Evidence Exome-chip association (n=5,169) with inferred molecular pathway

    PMID:28385800

    Open questions at the time
    • Molecular mechanism inferred, not experimentally tested in this study
    • ChREBP-FGF21 link not directly demonstrated for GKRP
  13. 2018 Medium

    Overexpression and human OGTT data connected GKRP levels to glucose-stimulated lactate via increased GCK protein, and identified glucagon as an inducer of GCKR expression.

    Evidence GKRP overexpression in HepG2 and primary hepatocytes, lactate/GCK quantification, glucagon treatment, human OGTT

    PMID:30375486

    Open questions at the time
    • Glucagon induction mechanism not detailed
    • In vivo relevance of lactate shift not established
  14. 2019 Medium

    In vivo zebrafish modeling showed population-specific rare GCKR variants promote hepatic fatty metamorphosis and ectopic fat, supporting a causal role in steatosis.

    Evidence Transgenic zebrafish expressing WT/mutant human GCKR, histology, mRNA quantification

    PMID:31369557

    Open questions at the time
    • Single-lab model
    • Mechanism of mRNA upregulation by mutants unexplained
  15. 2023 High

    A knockin mouse plus reconstitution defined P446L as compromising GKRP expressivity, nuclear GCK sequestration, and transcriptional counter-regulation, yielding lower glucose and altered cholesterol but, notably, not raised triglycerides.

    Evidence Adenoviral reconstitution in mouse/human GKRP-deficient hepatocytes, transcriptomics, P446L knockin phenotyping

    PMID:37031802

    Open questions at the time
    • Discrepancy with human triglyceride associations unresolved
    • Species-specific lipid responses not fully explained
  16. 2024 Medium

    Chronic pharmacology in GKRP-deficient mice showed GKRP status shapes glucokinase-activator durability and hepatic lipid side effects, framing GKRP as a determinant of drug response.

    Evidence Chronic AZD1656 dosing in Gckr-P446L and Gckr-del/wt mice with transcriptomics, lipid quantification, histology

    PMID:39173844

    Open questions at the time
    • Single-lab in vivo study
    • Translation to human GKA therapy not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether the SAPK/JNK kinase activity and the hepatic GKRP function reflect the same protein or a symbol collision, and how the enhancer-driven expression and coding P446L effects integrate quantitatively to set human triglyceride and glucose phenotypes, remain unresolved in this corpus.
  • No study reconciles the kinase-signaling and metabolic-regulator threads
  • Joint regulatory + coding variant model not built
  • Human vs mouse triglyceride discrepancy unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140313 molecular sequestering activity 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 3
Partners
GCKGSK3B

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Human GCKR cDNA encodes a 625 amino acid protein (predicted MW 68,700) with 88% amino acid identity to rat GCKR; the gene was mapped to chromosome 2p23 by fluorescent in situ hybridization and somatic cell hybrid analysis. cDNA cloning from HepG2 cells, FISH, somatic cell hybrid analysis Mammalian genome High 8589523
1998 Human GCKR gene spans 27 kb and consists of 19 exons; a common polymorphic variant in exon 15 at nucleotide 1400 changes amino acid residue 446 from proline (conserved in rat and Xenopus) to leucine. P1/YAC clone characterization, RT-PCR, RACE, RNase protection, SSCP screening Genomics High 9570959
1999 GCKR (the serine/threonine kinase, germinal center kinase-related) is activated downstream of Bcr-Abl via a Ras-dependent pathway and is required for Bcr-Abl-induced SAPK activation; GCKR co-immunoprecipitates with Bcr-Abl and is constitutively active in CML cell lines. Co-immunoprecipitation, kinase activity assays, dominant-negative GCKR expression, oncogenic Ras overexpression in cell lines Blood Medium 9949177
2000 Adaptor proteins CRK and CRKL associate with GCKR kinase through SH3 domain interactions (requiring a consensus SH3-binding motif between residues 387–395 and a second region 599–696 of GCKR); CRK/CRKL overexpression increases GCKR catalytic activity and SAPK activation in a Ras-dependent manner. Co-immunoprecipitation in HEK 293T cells and K562 cells, deletion/domain mapping, catalytic activity assays, antisense GCKR Blood Medium 10648385
2003 TNF-induced activation of GCKR kinase and the SAPK pathway requires both TRAF2 and the Ubc13/Uev1A ubiquitin-conjugating enzyme complex; TNF signaling leads to TRAF2 Lys63-linked polyubiquitination and GCKR oligomerization, ubiquitination, and activation. Dominant-negative Ubc13 expression, siRNA knockdown, co-immunoprecipitation, kinase activity assays in HEK 293T cells The Journal of biological chemistry Medium 12591926
2006 GCKR kinase is required for Wnt3a-induced JNK activation in B lymphocytes; GCKR also positively affects the canonical Wnt/β-catenin pathway by promoting GSK3β phosphorylation at Ser9 and increasing cytosolic β-catenin accumulation; Wnt signaling induces a physical interaction between GCKR and GSK3β. siRNA knockdown of GCKR in B cells, co-immunoprecipitation, Western blotting for GSK3β-pSer9 and β-catenin levels, JNK activation assay Molecular and cellular biology Medium 16914735
2009 The common P446L variant of GKRP (GCKR) shows attenuated response to physiologically relevant fructose-6-phosphate (F6P) concentrations compared to wild-type GKRP, resulting indirectly in increased glucokinase (GCK) activity; there is no difference in F1P-mediated regulation or dose-dependent GCK inhibition between WT and P446L-GKRP. In vitro enzymatic assay: recombinant human GCK and both WT and P446L-GKRP proteins; NADP+-coupled spectrophotometric kinetic assay Human molecular genetics High 19643913
2011 P446L-GKRP shows decreased nuclear localization, reduced ability to sequester GCK in the nucleus, and diminished direct interaction with GCK as measured by FRET, compared to wild-type GKRP; at high glucose, WT-GKRP–GCK interaction decreases but P446L-GKRP–GCK interaction is not further changed. Fluorescently tagged WT and P446L GKRP/GCK transiently transfected into HeLa cells and mouse primary hepatocytes; quantitative nuclear fluorescence; sensitized emission-based FRET efficiency measurement Diabetologia High 22038520
2013 Loss of the GCKR gene in vertebrate species correlates with hepatic glucokinase deficiency; GCKR stabilizes hepatic GCK protein levels and activity, and its absence (deletion or inactivating mutation) leads to reduced hepatic GCK protein and activity. Comparative genomics: identification and alignment of GCKR and GCKR-like sequences across vertebrate genomes; correlation with published hepatic GCK activity data PloS one Medium 23573289
2014 Eighteen rare non-synonymous GCKR variants were biochemically characterized; functionally deleterious rare variants collectively associate with hypertriglyceridemia, but rare variants did not co-segregate with triglyceride levels within individual families, demonstrating the low individual predictive value of rare GCKR variants. Biochemical and cell biological assays including a high-throughput-screening-based approach measuring all variant proteins simultaneously; family segregation analysis Human molecular genetics Medium 24879641
2015 Carriers of the GCKR rs1260326 TT risk genotype have higher fasting fractional and absolute hepatic de novo lipogenesis (DNL) rates and higher basal glucose oxidation compared to CC carriers, directly linking the variant's effect on glycolytic flux to increased hepatic lipid synthesis. Stable isotope tracer study: deuterium incorporation into VLDL-palmitate measured in obese adolescents during fasting and after oral carbohydrate challenge The Journal of clinical endocrinology and metabolism Medium 26043229
2017 A liver-specific FOXA2-regulated intragenic transcriptional enhancer at the GCKR locus (represented by rs780094, rs780095, rs780096) controls GCKR expression; the CGG haplotype (rs780094-C, rs780095-G, rs780096-G) shows higher FOXA2 binding, higher H3K27Ac levels, and higher GCKR transcription in human liver than the TAC haplotype. ENCODE histone modification/TF binding analysis, luciferase reporter assays in HepG2 and mouse primary hepatocytes, ChIP-qPCR, CRISPR-dCas9 transcriptional activator, allele-specific expression in human liver biopsies Genome medicine High 28683826
2017 The GCKR Leu446 missense variant (rs1260326) is significantly associated with circulating FGF21 levels; the mechanistic link is proposed to operate via increased GCK activity leading to elevated malonyl-CoA (inhibiting CPT1) and increased glucose-6-phosphate activating ChREBP, which drives FGF21 gene expression. Exome-chip association analysis (n=5,169 Chinese individuals); proposed molecular mechanism based on established GCK–malonyl-CoA–ChREBP pathway Diabetes Low 28385800
2018 The rs780094 C allele of GCKR is associated with lower lactate in fasting but higher lactate during hyperglycemia; increased GKRP expression in HepG2 cells and primary human hepatocytes raises lactate upon glucose stimulation by increasing GCK protein amount; glucagon induces GCKR expression in liver cells. OGTT-based human study; GKRP overexpression in HepG2 cells and primary human hepatocytes with lactate measurement and GCK protein quantification; glucagon treatment Scientific reports Medium 30375486
2019 Population-specific rare missense variants in GCKR in Punjabi Sikhs promote ectopic fat deposition; transgenic zebrafish expressing mutant GCKR show severe hepatocyte fatty metamorphosis and ~7-fold increased GCKR mRNA even without high-fat diet, while mutant fish on high-fat diet show greater fat accumulation than wild-type. Targeted resequencing, in vivo transgenic zebrafish models expressing human WT and mutant GCKR, liver histology, mRNA expression quantification PloS one Medium 31369557
2023 P446L substitution in mouse or human GKRP similarly compromises GKRP:446L protein expressivity, nuclear sequestration of glucokinase, and counter-regulation of gene expression; P446L knockin mice have lower liver glucokinase and GKRP protein; diet-challenged P446L mice exhibit lower blood glucose, raised blood cholesterol, and altered hepatic cholesterol homeostasis, but not raised blood triglycerides. Adenoviral-vector transfection of GKRP-deficient hepatocytes (mouse and human GKRP 446P/L), transcriptomics, P446L knockin mouse physiological phenotyping under dietary challenge, liver protein quantification Molecular metabolism High 37031802
2024 In GKRP-deficient mouse models (P446L knockin and Gckr-del/wt heterozygous), chronic glucokinase activator (AZD1656) efficacy declines after 19 weeks in P446L mice (despite maintained short-term efficacy) in conjunction with raised hepatic glucokinase activity; chronic treatment in Gckr-del/wt mice causes raised liver triglyceride and hepatocyte microvesicular steatosis. Chronic in vivo pharmacological study in Gckr-P446L and Gckr-del/wt mice; blood glucose measurement, liver transcriptomics, liver lipid quantification, histology Biochemical pharmacology Medium 39173844

Source papers

Stage 0 corpus · 89 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Human molecular genetics 327 19643913
2008 Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study. American journal of human genetics 275 18439548
2012 Hyperglycemia and a common variant of GCKR are associated with the levels of eight amino acids in 9,369 Finnish men. Diabetes 231 22553379
2011 Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology (Baltimore, Md.) 198 22105854
2008 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. Diabetes 165 18556336
2003 Tumor necrosis factor (TNF)-induced germinal center kinase-related (GCKR) and stress-activated protein kinase (SAPK) activation depends upon the E2/E3 complex Ubc13-Uev1A/TNF receptor-associated factor 2 (TRAF2). The Journal of biological chemistry 149 12591926
2007 The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol, reduced fasting and OGTT-related insulinaemia, and reduced risk of type 2 diabetes. Diabetologia 146 18008060
2013 Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third National Health and Nutrition Examination Survey. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 134 23416328
2014 Genetic variants in GCKR and PNPLA3 confer susceptibility to nonalcoholic fatty liver disease in obese individuals. The American journal of clinical nutrition 91 24477042
2011 Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk. Diabetologia 89 22038520
2015 Hepatic De Novo Lipogenesis in Obese Youth Is Modulated by a Common Variant in the GCKR Gene. The Journal of clinical endocrinology and metabolism 84 26043229
2009 Association of GCKR rs780094, alone or in combination with GCK rs1799884, with type 2 diabetes and related traits in a Han Chinese population. Diabetologia 63 19241058
2009 Combined effects of single-nucleotide polymorphisms in GCK, GCKR, G6PC2 and MTNR1B on fasting plasma glucose and type 2 diabetes risk. Diabetologia 58 19533084
2008 Interaction effect of genetic polymorphisms in glucokinase (GCK) and glucokinase regulatory protein (GCKR) on metabolic traits in healthy Chinese adults and adolescents. Diabetes 58 19073768
2010 Association of rs780094 in GCKR with metabolic traits and incident diabetes and cardiovascular disease: the ARIC Study. PloS one 54 20661421
2010 Genetic variation in the GCKR gene is associated with non-alcoholic fatty liver disease in Chinese people. Molecular biology reports 52 20625834
2008 Association between glucokinase regulatory protein (GCKR) and apolipoprotein A5 (APOA5) gene polymorphisms and triacylglycerol concentrations in fasting, postprandial, and fenofibrate-treated states. The American journal of clinical nutrition 45 19056598
2019 An intronic variant in the GCKR gene is associated with multiple lipids. Scientific reports 44 31308433
1995 Human glucokinase regulatory protein (GCKR): cDNA and genomic cloning, complete primary structure, and chromosomal localization. Mammalian genome : official journal of the International Mammalian Genome Society 34 8589523
2015 Effects of IGF2BP2, KCNQ1 and GCKR polymorphisms on clinical outcome in metastatic gastric cancer treated with EOF regimen. Pharmacogenomics 33 26115082
2011 Triglyceride response to an intensive lifestyle intervention is enhanced in carriers of the GCKR Pro446Leu polymorphism. The Journal of clinical endocrinology and metabolism 33 21525158
2012 Association between gout and polymorphisms in GCKR in male Han Chinese. Human genetics 32 22395765
2017 GCK, GCKR, FADS1, DGKB/TMEM195 and CDKAL1 Gene Polymorphisms in Women with Gestational Diabetes. Canadian journal of diabetes 31 28359772
2011 Variants of GCKR affect both β-cell and kidney function in patients with newly diagnosed type 2 diabetes: the Verona newly diagnosed type 2 diabetes study 2. Diabetes care 31 21411509
2010 Glucokinase-activating GCKR polymorphisms increase plasma levels of triglycerides and free fatty acids, but do not elevate cardiovascular risk in the Ludwigshafen Risk and Cardiovascular Health Study. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 31 20352598
2010 GCKR gene functional variants in type 2 diabetes and metabolic syndrome: do the rare variants associate with increased carotid intima-media thickness? Cardiovascular diabetology 30 21114848
2021 Contribution of Rs780094 and Rs1260326 Polymorphisms in GCKR Gene to Non-alcoholic Fatty Liver Disease: A Meta-Analysis Involving 26,552 Participants. Endocrine, metabolic & immune disorders drug targets 27 33243135
2018 FTO, GCKR, CDKAL1 and CDKN2A/B gene polymorphisms and the risk of gestational diabetes mellitus: a meta-analysis. Archives of gynecology and obstetrics 27 30074065
2017 Identification and characterization of a FOXA2-regulated transcriptional enhancer at a type 2 diabetes intronic locus that controls GCKR expression in liver cells. Genome medicine 26 28683826
2006 The mitogen-activated protein kinase kinase kinase kinase GCKR positively regulates canonical and noncanonical Wnt signaling in B lymphocytes. Molecular and cellular biology 26 16914735
1999 GCKR links the Bcr-Abl oncogene and Ras to the stress-activated protein kinase pathway. Blood 26 9949177
2012 Associations of apolipoprotein A5 (APOA5), glucokinase (GCK) and glucokinase regulatory protein (GCKR) polymorphisms and lifestyle factors with the risk of dyslipidemia and dysglycemia in Japanese - a cross-sectional data from the J-MICC Study. Endocrine journal 25 22517333
2011 Associations of common polymorphisms in GCKR with type 2 diabetes and related traits in a Han Chinese population: a case-control study. BMC medical genetics 23 21569451
2021 GCKR common functional polymorphisms are associated with metabolic syndrome and its components: a 10-year retrospective cohort study in Iranian adults. Diabetology & metabolic syndrome 21 33602293
2014 Inheritance of rare functional GCKR variants and their contribution to triglyceride levels in families. Human molecular genetics 21 24879641
1998 Organization of the human glucokinase regulator gene GCKR. Genomics 21 9570959
2016 The GCKR Gene Polymorphism rs780094 is a Risk Factor for Gestational Diabetes in a Brazilian Population. Journal of clinical laboratory analysis 20 27554451
2000 Adaptor proteins CRK and CRKL associate with the serine/threonine protein kinase GCKR promoting GCKR and SAPK activation. Blood 20 10648385
2022 Pleiotropic Effects of Common and Rare GCKR Exonic Mutations on Cardiometabolic Traits. Genes 19 35328045
2019 Association of GCKR Gene Polymorphisms with the Risk of Nonalcoholic Fatty Liver Disease and Coronary Artery Disease in a Chinese Northern Han Population. Journal of clinical and translational hepatology 19 31915598
2016 Association between PNPLA3 (rs738409), LYPLAL1 (rs12137855), PPP1R3B (rs4240624), GCKR (rs780094), and elevated transaminase levels in overweight/obese Mexican adults. Molecular biology reports 19 27752939
2015 Polymorphisms in the GCKR are associated with serum lipid traits, the risk of coronary artery disease and ischemic stroke. International journal of clinical and experimental medicine 18 26379859
2015 GCKR polymorphism influences liver fat content in patients with type 2 diabetes. Acta diabetologica 17 25976242
2019 Targeted sequencing of candidate genes of dyslipidemia in Punjabi Sikhs: Population-specific rare variants in GCKR promote ectopic fat deposition. PloS one 16 31369557
2018 Gene variants in AKT1, GCKR and SOCS3 are differentially associated with metabolic traits in Mexican Amerindians and Mestizos. Gene 16 30176313
2017 An Exome-Chip Association Analysis in Chinese Subjects Reveals a Functional Missense Variant of GCKR That Regulates FGF21 Levels. Diabetes 16 28385800
2013 Evolution of hepatic glucose metabolism: liver-specific glucokinase deficiency explained by parallel loss of the gene for glucokinase regulatory protein (GCKR). PloS one 15 23573289
2023 The GCKR-P446L gene variant predisposes to raised blood cholesterol and lower blood glucose in the P446L mouse-a model for GCKR rs1260326. Molecular metabolism 14 37031802
2015 Functional variants of lipid level modifier MLXIPL, GCKR, GALNT2, CILP2, ANGPTL3 and TRIB1 genes in healthy Roma and Hungarian populations. Pathology oncology research : POR 14 25573592
2013 GCK, GCKR polymorphisms and risk of chronic kidney disease in Japanese individuals: data from the J-MICC Study. Journal of nephrology 14 24535998
2023 Waist circumference mediates the association between rs1260326 in GCKR gene and the odds of lean NAFLD. Scientific reports 13 37081070
2019 Association between lncRNA and GCKR gene in type 2 diabetes mellitus. Clinica chimica acta; international journal of clinical chemistry 12 31756311
2016 Type 1 Hyperlipoproteinemia Due to Compound Heterozygous Rare Variants in GCKR. The Journal of clinical endocrinology and metabolism 12 27403930
2005 Novel polymorphisms in the GCKR gene and their influence on glucose and insulin levels in a Danish twin population. Diabetic medicine : a journal of the British Diabetic Association 12 16401311
2015 The n-3 long-chain PUFAs modulate the impact of the GCKR Pro446Leu polymorphism on triglycerides in adolescents. Journal of lipid research 11 26136510
2014 Association of the GCKR rs780094 polymorphism with metabolic traits including carotid intima-media thickness in Japanese community-dwelling men, but not in women. Clinical chemistry and laboratory medicine 10 23989113
2013 GCKR variants increase triglycerides while protecting from insulin resistance in Chinese children. PloS one 10 23383164
2022 Evaluating machine learning-powered classification algorithms which utilize variants in the GCKR gene to predict metabolic syndrome: Tehran Cardio-metabolic Genetics Study. Journal of translational medicine 9 35397593
2022 GCKR and GCK polymorphisms are associated with increased risk of end-stage kidney disease in Chinese patients with type 2 diabetes: The Hong Kong Diabetes Register (1995-2019). Diabetes research and clinical practice 9 36243233
2017 A modified response of NAFLD patients with non-significant fibrosis in nutritional counseling according to GCKR rs1260326. European journal of nutrition 9 28695325
2015 Discrete associations of the GCKR variant with metabolic risk in a Chinese population: longitudinal change analysis. Diabetologia 9 26515422
2011 Common functional variants of APOA5 and GCKR accumulate gradually in association with triglyceride increase in metabolic syndrome patients. Molecular biology reports 9 21643755
2023 Prevalence of GCKR rs1260326 Variant in Subjects with Obesity Associated NAFLD and T2DM: A Case-Control Study in South Punjab, Pakistan. Journal of obesity 8 37829557
2013 Associations between a polymorphism in the pleiotropic GCKR and Age-related phenotypes: the HALCyon programme. PloS one 8 23894584
2022 Association of Alcohol Use Disorder Risk With ADH1B, DRD2, FAAH, SLC39A8, GCKR, and PDYN Genetic Polymorphisms. In vivo (Athens, Greece) 7 36099111
2015 Early gene-diet interaction between glucokinase regulatory protein (GCKR) polymorphism, vegetable and fish intakes in modulating triglyceride levels in healthy adolescents. Nutrition, metabolism, and cardiovascular diseases : NMCD 7 26234566
2023 GCKR and ADIPOQ gene polymorphisms in women with gestational diabetes mellitus. Acta diabetologica 6 37524927
2018 Functional Variant in the GCKR Gene Affects Lactate Levels Differentially in the Fasting State and During Hyperglycemia. Scientific reports 6 30375486
2010 GCKR mutations in Japanese families with clustered type 2 diabetes. Molecular genetics and metabolism 6 21236713
2024 Compromised chronic efficacy of a glucokinase activator AZD1656 in mouse models for common human GCKR variants. Biochemical pharmacology 5 39173844
2023 Association of GCK (rs1799884), GCKR (rs780094), and G6PC2 (rs560887) Gene Polymorphisms with Type 2 Diabetes among Malay Ethnics. Global medical genetics 5 36703777
2019 Relationship between N,N-dimethylformamide exposure, PNPLA3, GCKR, COL13A1 and TM6SF2 genes, and liver injury. Ecotoxicology and environmental safety 5 30616151
2019 The relationship among GNB3 rs5443, PNPLA3 rs738409, GCKR rs780094 gene polymorphisms, type of maternal gestational weight gain and neonatal outcomes (STROBE-compliant article). Medicine 5 31305457
2014 Genetic variability of GCKR alters lipid profiles in children with monogenic and autoimmune diabetes. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 5 24918535
2014 [Association between rs780094 polymorphism in GCKR and plasma lipid levels in children and adolescents]. Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi 4 25174460
2011 Glucokinase regulatory protein (GCKR) gene rs4425043 polymorphism is associated with overweight and obesity in Chinese women. Lipids 4 21318467
2024 Sex-specific impact of GCKR rs1260326 polymorphism on metabolic traits in an older Japanese population: the Bunkyo Health Study. Therapeutic advances in endocrinology and metabolism 3 39346030
2023 Regularized Machine Learning Models for Prediction of Metabolic Syndrome Using GCKR, APOA5, and BUD13 Gene Variants: Tehran Cardiometabolic Genetic Study. Cell journal 2 37641415
2023 Interaction between the GCKR rs1260326 variant and serum HDL cholesterol contributes to HOMA-β and ISIMatusda in the middle-aged T2D individuals. Journal of human genetics 2 37648893
2023 Relationship between GCKR gene rs780094 polymorphism and type 2 diabetes with albuminuria. World journal of diabetes 2 38222779
2025 Contribution of Type 2 Diabetes Susceptible Gene GCKR Polymorphisms Rs780094 and Rs1260326 to Gestational Diabetes Mellitus: A Meta-Analysis. Endocrine, metabolic & immune disorders drug targets 1 39806965
2025 Contribution of PNPLA3, GCKR, MBOAT7, NCAN, and TM6SF2 Genetic Variants to Hepatocellular Carcinoma Development in Mexican Patients. International journal of molecular sciences 1 40806538
2016 [Association of GCKR gene polymorphisms and type 2 diabetes among ethnic Uygurs]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 27455017
2026 GCKR genetic variants and circulating FGF21 identify a metabolic risk signature in metabolic dysfunction-associated steatotic liver disease. BMC gastroenterology 0 41975319
2026 Analysis of PNPLA3, TM6SF2 and GCKR gene polymorphisms in patients with metabolic dysfunction-associated steatohepatitis treated with probiotics ‒ An exploratory study. Nutricion hospitalaria 0 42023869
2026 Association of GCKR and GLIS3 gene polymorphisms with gestational diabetes mellitus: A case-control study. The Indian journal of medical research 0 42024906
2025 The association between genetic polymorphisms in GCKR and gout: A systematic review and meta-analysis. Medicine 0 40419928
2025 Glucokinase Regulatory Protein (GCKR) Links Metabolic Reprogramming With Immune Exclusion: Insights From a Pan-Cancer Analysis and Gastric Cancer Validation. Human mutation 0 41235343
2021 Association of GCKR Gene Polymorphisms with Metabolic Syndrome in a Han Population from Northeast China. Clinical laboratory 0 34655193

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