Affinage

GCK

Mitogen-activated protein kinase kinase kinase kinase 2 · UniProt Q12851

Length
820 aa
Mass
91.6 kDa
Annotated
2026-06-10
100 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Glucokinase (GCK) is a glucose-phosphorylating enzyme whose kinetic and conformational properties make it the rate-setting glucose sensor of pancreatic beta-cells and a key node in hepatic glucose metabolism (PMID:10455021, PMID:22291974). Its function depends on an allosteric mechanism in which an intrinsically disordered loop samples multiple conformations on the nanosecond timescale; glucose binding and disease mutations reshape the population of these states to generate cooperative (sigmoidal) kinetics, and a discrete allosteric site couples to both the endogenous activator fructose-2,6-bisphosphate and synthetic activators such as RO-28-1675 (PMID:32023434, PMID:34532767). Enzyme output is modulated by binding to glucokinase regulatory protein (GKRP), and mutations can either strengthen or abolish this interaction (PMID:17186219, PMID:30257192, PMID:34532767). Disease-causing mutations act through three convergent routes: reduced catalytic efficiency, decreased thermostability that drives misfolding, dimerization, aggregation, and proteasomal/lysosomal degradation, or altered GKRP binding (PMID:22820548, PMID:24001579, PMID:30257192); thermostability rather than kinetic defect alone is the principal determinant of clinical severity in homozygous, early-onset cases (PMID:25015100), whereas mutations at the allosteric activator site that increase glucose affinity cause congenital hyperinsulinism (PMID:18450771, PMID:34532767). In the liver, GCK transcription is controlled by a promoter retinoic acid responsive element bound by RARalpha, HNF4alpha, and COUP-TFII, through which retinoids synergize with insulin to induce expression, and is epigenetically silenced by age-related promoter hypermethylation (PMID:18496667, PMID:19173678, PMID:24973045). In cardiomyocytes GCK is repressed by the transcription factor Hmbox1, and its de-repression improves glucose metabolism and protects against ischemia/reperfusion injury (PMID:38708602).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Established that distinct GCK point mutations produce mechanistically distinct defects, separating kinetic impairment from protein instability as causes of altered insulin secretion.

    Evidence Adenoviral expression of GCK mutants in beta-HC9 cells with in vitro kinetics, Western blot, and glucose-stimulated insulin secretion

    PMID:10455021

    Open questions at the time
    • Did not resolve the structural basis of instability
    • Limited to a few mutants in one beta-cell line
  2. 2006 High

    Demonstrated that some MODY2 mutations impair function not by kinetics but by destabilizing protein and strengthening inhibitory GKRP binding, broadening the disease mechanism.

    Evidence Recombinant kinetics, thermal stability, and pull-down assays against GCKR and PFKFB1

    PMID:17186219

    Open questions at the time
    • Physiological consequence of enhanced GKRP binding in vivo not shown
    • PFKFB1 interaction role left undefined
  3. 2008 High

    Localized activating mutations to a discrete allosteric activator site and linked increased glucose affinity to congenital hyperinsulinism.

    Evidence Kinetic characterization of recombinant activating GCK mutants

    PMID:18450771

    Open questions at the time
    • Mechanism of conformational activation not resolved at this stage
    • No structural data on the activator site
  4. 2008 High

    Showed that hepatic Gck is epigenetically silenced by age-related promoter hypermethylation, providing a non-genetic mechanism of expression control.

    Evidence Bisulphite sequencing, qPCR, kinase activity assay, and 5-Aza-CdR demethylation in rat hepatocytes

    PMID:18496667

    Open questions at the time
    • Methyltransferases responsible not identified
    • Rat liver only; human relevance not tested here
  5. 2008 Medium

    Expanded the catalog of catalytically impairing MODY2 mutations and correlated severity with active-site structural disruption.

    Evidence Recombinant expression and enzymatic activity assays for six novel mutations

    PMID:18322640

    Open questions at the time
    • Single activity-assay method without orthogonal stability data
    • No cellular validation
  6. 2009 High

    Defined retinoids as insulin-synergizing inducers of hepatic Gck acting through RAR/RXR, independent of SREBP-1c.

    Evidence Primary rat hepatocytes, RAR/RXR pharmacological inhibition, and in vivo vitamin A deficiency/rescue

    PMID:19173678

    Open questions at the time
    • Direct promoter element not yet mapped at this stage
    • Did not identify all cofactors
  7. 2012 High

    Identified protein misfolding, aggregation, and quality-control degradation as a disease mechanism for catalytically near-normal GCK-MODY mutations in the F260-L270 loop.

    Evidence Stable expression in HEK293 and MIN6 cells, pulse-chase, fractionation, and SDS-resistant dimer detection

    PMID:22820548

    Open questions at the time
    • Aggregation behaviour in primary beta-cells not assessed
    • Chaperones mediating degradation not identified
  8. 2012 High

    Showed an allosteric-site mutation can reshape the glucose-sensor conformational equilibrium rather than simply lowering activity, linking mutations to conformational state.

    Evidence Recombinant kinetics with competitive inhibitor and allosteric activator probing

    PMID:22291974

    Open questions at the time
    • Conformational states inferred indirectly, not directly observed
    • No structural snapshots
  9. 2013 High

    Provided an atomic-level rationale for misfolding by showing a single hydrogen-bond disruption destabilizes the F260-L271 loop to drive aggregation.

    Evidence Stable expression in HEK293/MIN6, pulse-chase, proteasome/lysosome inhibition, and structural modelling

    PMID:24001579

    Open questions at the time
    • Modelled rather than experimentally determined structure of the mutant
    • Relative proteasome vs lysosome contribution not quantified
  10. 2014 High

    Established protein thermostability as the dominant determinant of clinical severity in homozygous early-onset disease, outweighing kinetic defects.

    Evidence Recombinant kinetics plus differential scanning fluorimetry correlated with clinical grading in 30 patients

    PMID:25015100

    Open questions at the time
    • Correlation does not establish the in vivo degradation rate
    • Heterozygous phenotype predictors not addressed
  11. 2014 High

    Mapped the hepatic Gck RARE and its bound transcription factors, mechanistically anchoring retinoid/insulin regulation to specific cis and trans elements.

    Evidence EMSA, ChIP, adenoviral overexpression of RARalpha/HNF4alpha/COUP-TFII, and promoter mutagenesis in rat hepatocytes

    PMID:24973045

    Open questions at the time
    • Human promoter not directly validated
    • RXRalpha occupancy role left unresolved
  12. 2018 High

    Integrated kinetics, thermostability, and GKRP-binding measurements across many mutations to show GKRP interaction can be variably enhanced, reduced, or abolished.

    Evidence Recombinant kinetics, thermostability, and GKRP pull-down for novel and known variants

    PMID:30257192

    Open questions at the time
    • Cellular consequences of altered GKRP binding not tested
    • Structural basis of binding changes not resolved
  13. 2019 Medium

    Added quantitative kinetic and thermostability profiling of additional MODY2 variants, distinguishing functionally damaging from neutral substitutions.

    Evidence Recombinant E. coli expression with kinetic and thermostability assays

    PMID:30592380

    Open questions at the time
    • No orthogonal cellular or binding assays
    • Variants R250H/R275H lacked a measurable defect, leaving pathogenicity unexplained
  14. 2020 High

    Directly demonstrated that nanosecond loop dynamics underlie GCK cooperativity, providing the physical mechanism of the glucose sensor.

    Evidence Unnatural amino acid incorporation, time-resolved fluorescence, and 19F NMR with disease-mutation validation

    PMID:32023434

    Open questions at the time
    • Dynamics studied on isolated protein, not in cellular context
    • Coupling of dynamics to catalytic turnover not fully quantified
  15. 2021 High

    Linked a specific activating residue to conformational rearrangement and additive responsiveness to both endogenous and synthetic allosteric activators.

    Evidence Recombinant kinetics, allosteric activator/inhibitor assays, translocation and insulin secretion assays, and structural modelling of V455L vs V455M

    PMID:34532767

    Open questions at the time
    • Structural mechanism modelled rather than directly determined
    • Long-term clinical consequences of the variant not addressed
  16. 2021 Medium

    Used Drosophila orthologs to connect GCK loss to MODY-like hyperglycemia and downstream oxidative DNA damage, extending function beyond enzyme kinetics to systemic genomic consequences.

    Evidence RNAi knockdown of Hex-A/Hex-C, insulin secretion, ROS/AGE quantification, chromosome aberration analysis, and vitamin B6 rescue

    PMID:33477627

    Open questions at the time
    • Ortholog model, not mammalian GCK directly
    • Relevance of the genomic-instability axis to human disease untested
  17. 2024 High

    Identified Hmbox1 as a cardiomyocyte-specific transcriptional repressor of Gck and showed GCK de-repression is cardioprotective, defining a tissue role beyond beta-cell/liver glucose sensing.

    Evidence AAV9 knockdown and cardiomyocyte-specific knockout in mice, RNA-seq, promoter binding assays, Seahorse metabolism, and in vivo I/R injury model

    PMID:38708602

    Open questions at the time
    • Direct Hmbox1 binding to the Gck promoter detail limited
    • Whether GCK alone is sufficient for protection not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the structurally defined nanosecond dynamics, GKRP regulation, and tissue-specific transcriptional control are integrated to set glucose-sensing thresholds in vivo remains unresolved.
  • No in-cell or in-vivo measurement of GCK conformational dynamics
  • Human hepatic/cardiac transcriptional circuitry only partially mapped
  • Quantitative link between thermostability, degradation kinetics, and beta-cell function incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140299 molecular sensor activity 3 GO:0140657 ATP-dependent activity 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1430728 Metabolism 3
Partners
COUP-TFIIGCKRHMBOX1HNF4ARARARXRA

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Recombinant adenovirus-expressed human islet glucokinase (GCK) mutants E70K, V203A, and E300K show distinct kinetic defects in beta-HC9 cells: E70K has half the glucose affinity of wild-type; V203A shows decreased catalytic activity and 8-fold increase in glucose S0.5; E300K has near-normal glucose affinity but 10-fold reduced enzyme activity with markedly reduced protein levels (instability mutation); activating mutant V455M retains wild-type activity but has markedly reduced S0.5. These cell-biological effects on glucose-stimulated insulin release correlated with kinetic and expression data. Recombinant adenovirus transduction of beta-HC9 cells, kinetic analysis in vitro, Western blot, glucose-stimulated insulin secretion assay The Biochemical journal High 10455021
2006 MODY2-associated GCK mutations impair enzyme function through distinct mechanisms: inserN161 fully inactivates GCK; M235V and R308W partially impair enzymatic activity; R397L leaves kinetics nearly unaffected. The R308W mutation causes protein instability and increases strength of interaction with glucokinase regulatory protein (GCKR/GKRP), as shown by pull-down assay. None of the mutations affected GCK interaction with PFKFB1. Recombinant protein expression, kinetic analysis, thermal stability assay, pull-down assay with GCKR and PFKFB1 Diabetologia High 17186219
2008 Activating GCK mutations (S64Y, T65I, W99R, A456V) cluster at the allosteric activator site and cause congenital hyperinsulinism. The novel S64Y mutation markedly increases glucose affinity (S0.5 reduced from 7.39 to 1.49 mmol/l), yielding a relative activity index ~22-fold above wild-type. Kinetic characterization of recombinant mutant GCK proteins expressed in bacteria European journal of endocrinology High 18450771
2008 Age-related hypermethylation of CpG sites in the hepatic Gck promoter is negatively associated with Gck mRNA expression and GCK kinase activity in rats. Treatment of rat primary hepatocytes with the demethylating agent 5-aza-2'-deoxycytidine (5-Aza-CdR) caused a fourfold increase in Gck expression, establishing a causal link between promoter methylation and transcriptional repression. Bisulphite sequencing, real-time PCR, kinase activity assay, pharmacological demethylation (5-Aza-CdR) in primary hepatocytes Diabetologia High 18496667
2009 Retinoids (retinol and retinal) synergize with insulin to induce hepatic Gck expression through activation of both RAR and RXR nuclear receptors, independently of SREBP-1c. Inhibition of RAR activation completely abolished the retinoid effect. Vitamin A deficiency in rats significantly reduced hepatic GCK specific activity and Gck mRNA, and intraperitoneal retinoic acid rescued Gck expression in VAD rats. Primary rat hepatocyte culture, real-time PCR, GCK activity assay, pharmacological inhibition of RAR/RXR, in vivo vitamin A deficiency/supplementation model in rats The Biochemical journal High 19173678
2012 MODY2 GCK mutations S263P and G264S in the F260-L270 loop produce misfolded proteins with increased degradation rates and propensity to self-associate into SDS-resistant dimers and detergent-insoluble aggregates when stably expressed in HEK293 cells and MIN6 beta-cells. Protein quality control machinery (proteasomal/lysosomal) mediates their degradation. This establishes protein misfolding and aggregation as a disease mechanism for catalytically 'normal' GCK-MODY mutations. Stable overexpression in HEK293 and MIN6 cells, pulse-chase experiments, subcellular fractionation, SDS-PAGE for dimer detection Biochimica et biophysica acta High 22820548
2013 The MODY2-associated GCK mutation R275C produces misfolded, unstable protein that forms dimers and aggregates when expressed in HEK293 cells and MIN6 beta-cells. Its degradation involves both lysosomal and proteasomal quality control systems. Mechanistically, the R275C substitution breaks a hydrogen bond between R275 and the carbonyl oxygen of D267, destabilizing the F260-L271 loop and promoting dimerization/aggregation. Stable expression in HEK293 and MIN6 cells, pulse-chase experiments, proteasome/lysosome inhibitor treatments, structural modelling Molecular and cellular endocrinology High 24001579
2014 For homozygous GCK mutations causing neonatal/childhood-onset diabetes, protein thermostability (measured as relative stability index, RSI) is the primary determinant of clinical severity (r²=0.74, P=0.002), whereas kinetic defects alone do not correlate with phenotype (r²=0.05, P=0.39). Two later-onset homozygous mutations exhibited increased thermostability, consistent with this model. Recombinant mutant GCK protein expression, kinetic analysis, thermostability assay (differential scanning fluorimetry), clinical severity grading in 30 patients with 19 unique mutations Human molecular genetics High 25015100
2012 Five MODY2 GCK missense mutations (p.Ile130Thr, p.Asp205His, p.Gly223Ser, p.His416Arg, p.Ala449Thr) impair GCK kinetic parameters. Notably, p.Ala449Thr (in the allosteric activator site) does not significantly reduce the activity index but dramatically alters glucose sensor parameters: Kcat is reduced ~15-fold while glucose affinity is increased ~6-fold (S0.5 = 1.33 vs 7.86 mM) with loss of cooperativity. Competitive inhibitor and allosteric activator experiments indicate this mutation alters the conformational equilibrium of GCK. Recombinant GST-GCK mutant protein expression in bacteria, kinetic analysis, competitive inhibitor and allosteric activator assays PloS one High 22291974
2014 A retinoic acid responsive element (RARE) in the hepatic Gck promoter interacts with RARα, RXRα, HNF4α, and COUP-TFII. Chromatin immunoprecipitation demonstrated that adenovirus-mediated overexpression of RARα, HNF4α, and COUP-TFII (but not RXRα) significantly increased their occupancy at the hepatic Gck promoter. Overexpression of RARα, HNF4α, and COUP-TFII (but not RXRα) affected RA- and insulin-mediated Gck expression in primary rat hepatocytes. Single nucleotide mutations in the RARE abolished promoter activation by retinoic acid. EMSA, ChIP assay, recombinant adenovirus overexpression, promoter mutagenesis, primary rat hepatocyte culture The Journal of nutritional biochemistry High 24973045
2018 Five novel GCK mutations (F195S, I211T, V222D, E236G, K458R) identified in Chinese MODY2 patients impair glucokinase through reduced catalytic efficiency and decreased thermostability. Additionally, interaction with glucokinase regulatory protein (GKRP) was significantly enhanced for I211T, I159V, T49N, and K458R; reduced for F195S and M381T; and completely abolished for A188T. V222D and E236G cause full inactivation via severe structural disruption. Recombinant protein expression, kinetic analysis, thermostability assay, GKRP interaction assay (pull-down) Metabolism: clinical and experimental High 30257192
2020 Nanosecond-timescale dynamics of human GCK were mapped using unnatural amino acid incorporation, time-resolved fluorescence, and 19F NMR. An intrinsically disordered loop within GCK samples multiple conformations in the unliganded state. Glucose binding and disease-associated mutations that suppress cooperativity alter the number and/or relative population of these conformational states, establishing nanosecond dynamics as part of the mechanism of GCK cooperativity. Unnatural amino acid incorporation, time-resolved fluorescence spectroscopy, 19F NMR spectroscopy Biophysical journal High 32023434
2019 Five GCK mutations (R43C, K169N, R191W, E221K, A379E) in Chinese MODY2 families show reduced enzyme activity with relative activity indexes of ~0.001–0.5 compared to wild-type (1.0), and decreased thermostability. For R250H and R275H variants, no significant difference in enzyme activity or thermal stability was detected compared to wild-type. Recombinant E. coli expression of mutant GCK, kinetic analysis, thermostability assay Journal of diabetes investigation Medium 30592380
2021 The novel gain-of-function GCK variant p.Val455Leu (V455L) significantly increases glucose affinity (S0.5: 2.4 vs 7.6 mmol/l wild-type) and shows additive susceptibility to both the endogenous activator fructose-2,6-bisphosphate and the synthetic allosteric activator RO-28-1675. GKRP binding is unimpaired for V455L, but reduced for V455M. Structural analyses implicated residue 455 in conformational rearrangements between inactive and active GCK states and in allosteric activation. Kinetic analysis of recombinant mutant GCK, allosteric activator/inhibitor assays, intracellular translocation assay, insulin secretion measurement, structural modelling Diabetologia High 34532767
2024 Hmbox1 functions as a transcriptional repressor of Gck in cardiomyocytes. Inhibition of Hmbox1 transcriptionally upregulates Gck, leading to improved mitochondrial respiration, glycolysis, reduced apoptosis, and cardioprotection after ischemia/reperfusion injury. ETS1 was identified as an upstream negative regulator of Hmbox1 transcription. These effects were confirmed by AAV9-mediated Hmbox1 knockdown and cardiomyocyte-specific Hmbox1 knockout in mice, with RNA sequencing, promoter prediction, and binding assays identifying Gck as a downstream effector. AAV9-mediated knockdown, cardiomyocyte-specific knockout (Cre-lox), RNA sequencing, promoter binding assays, Akt/mTOR/P70S6K pathway analysis, Seahorse metabolic assay, in vivo cardiac I/R injury model Circulation High 38708602
2021 Silencing the Drosophila GCK orthologs Hex-A (expressed in insulin-producing cells) and Hex-C (expressed in fat body) results in MODY-2-like hyperglycemia. Hex-A is essential for insulin secretion, and Hex-A expression is required for Hex-C expression. Knockdown of either ortholog increases chromosome aberrations, reactive oxygen species, and advanced glycation end-products. Treatment with antioxidant vitamin B6 rescued chromosome aberrations, while a B6 inhibitor enhanced genomic instability, linking hyperglycemia-induced oxidative stress to DNA damage. Targeted RNAi knockdown in Drosophila, immunofluorescence for tissue expression, insulin secretion assay, ROS measurement, AGE quantification, chromosome aberration analysis, pharmacological rescue with vitamin B6 International journal of molecular sciences Medium 33477627
2008 Biochemical characterization of six novel MODY2-associated GCK missense mutations (Y61S, V182L, C233R, E265K, A379V, K420E) shows all produce enzymes with reduced activity to varying degrees. C233R, affecting a critical active-site residue, renders GCK with undetectable enzymatic activity. Mutation severity correlates with structural changes at the mutated position. Recombinant mutant GCK expression, enzymatic activity assay Journal of human genetics Medium 18322640

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Human mutation 384 19790256
2003 Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy. Human mutation 200 14517946
2013 De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed. Diabetologia 90 24323243
2007 Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain. Clinical endocrinology 81 17573900
2002 Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2. Molecular and cellular biology 78 11784851
2022 Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. American journal of human genetics 76 36257325
2008 Hypermethylation of hepatic Gck promoter in ageing rats contributes to diabetogenic potential. Diabetologia 66 18496667
2016 GCK-MODY in the US National Monogenic Diabetes Registry: frequently misdiagnosed and unnecessarily treated. Acta diabetologica 64 27106716
2010 Common polymorphisms in MTNR1B, G6PC2 and GCK are associated with increased fasting plasma glucose and impaired beta-cell function in Chinese subjects. PloS one 64 20628598
1992 A polymorphic (CA)n repeat element maps the human glucokinase gene (GCK) to chromosome 7p. Genomics 64 1740341
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
2008 Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation. European journal of endocrinology 63 18450771
2004 A series of maturity onset diabetes of the young, type 2 (MODY2) mouse models generated by a large-scale ENU mutagenesis program. Human molecular genetics 63 15102714
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
2005 GCK-3, a newly identified Ste20 kinase, binds to and regulates the activity of a cell cycle-dependent ClC anion channel. The Journal of general physiology 55 15684092
2008 Long-term follow-up of oral glucose tolerance test-derived glucose tolerance and insulin secretion and insulin sensitivity indexes in subjects with glucokinase mutations (MODY2). Diabetes care 54 18411240
2007 Partial and whole gene deletion mutations of the GCK and HNF1A genes in maturity-onset diabetes of the young. Diabetologia 54 17828387
2024 Inhibition of Hmbox1 Promotes Cardiomyocyte Survival and Glucose Metabolism Through Gck Activation in Ischemia/Reperfusion Injury. Circulation 52 38708602
1998 The germinal center kinase (GCK)-related protein kinases HPK1 and KHS are candidates for highly selective signal transducers of Crk family adapter proteins. Oncogene 51 9788432
2010 The fatty acid synthase fasn-1 acts upstream of WNK and Ste20/GCK-VI kinases to modulate antimicrobial peptide expression in C. elegans epidermis. Virulence 50 21178429
2006 Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity. Diabetologia 49 17186219
2007 The GCK II and III subfamilies of the STE20 group kinases. Frontiers in bioscience : a journal and virtual library 46 17127342
2014 Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability. Human molecular genetics 45 25015100
2008 Diagnostic screening of MODY2/GCK mutations in the Norwegian MODY Registry. Pediatric diabetes 44 18399931
2000 Maternal diabetes alters birth weight in glucokinase-deficient (MODY2) kindred but has no influence on adult weight, height, insulin secretion or insulin sensitivity. Diabetologia 44 10990085
1999 Cell-biological assessment of human glucokinase mutants causing maturity-onset diabetes of the young type 2 (MODY-2) or glucokinase-linked hyperinsulinaemia (GK-HI). The Biochemical journal 42 10455021
2014 Less but better: cardioprotective lipid profile of patients with GCK-MODY despite lower HDL cholesterol level. Acta diabetologica 37 24549415
2012 Glucokinase (GCK) mutations and their characterization in MODY2 children of southern Italy. PloS one 37 22761713
2012 Metabolite profiling reveals normal metabolic control in carriers of mutations in the glucokinase gene (MODY2). Diabetes 37 23139355
2009 Clinical heterogeneity in monogenic diabetes caused by mutations in the glucokinase gene (GCK-MODY). Diabetes care 37 19903754
2024 Glucokinase (GCK) in diabetes: from molecular mechanisms to disease pathogenesis. Cellular & molecular biology letters 36 39245718
2018 Management and pregnancy outcomes of women with GCK-MODY enrolled in the US Monogenic Diabetes Registry. Acta diabetologica 36 30535721
2009 Retinoids synergize with insulin to induce hepatic Gck expression. The Biochemical journal 35 19173678
2003 The direct activation of MIK, a germinal center kinase (GCK)-like kinase, by MARK, a maize atypical receptor kinase, suggests a new mechanism for signaling through kinase-dead receptors. The Journal of biological chemistry 35 12966093
2014 GCK gene-body hypomethylation is associated with the risk of coronary heart disease. BioMed research international 34 24696842
2001 Routine mutation screening of HNF-1alpha and GCK genes in MODY diagnosis: how effective are the techniques of DHPLC and direct sequencing used in combination? Diabetologia 33 11440371
2000 Role of TRAF2/GCK in melanoma sensitivity to UV-induced apoptosis. Oncogene 33 10702802
2017 GCK, GCKR, FADS1, DGKB/TMEM195 and CDKAL1 Gene Polymorphisms in Women with Gestational Diabetes. Canadian journal of diabetes 31 28359772
2005 Ste20/GCK kinase Nak1/Orb3 polarizes the actin cytoskeleton in fission yeast during the cell cycle. Journal of cell science 31 15731009
2020 Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons. Proceedings of the National Academy of Sciences of the United States of America 30 33318207
2013 Identification of candidate children for maturity-onset diabetes of the young type 2 (MODY2) gene testing: a seven-item clinical flowchart (7-iF). PloS one 29 24244580
2009 Opposite clinical phenotypes of glucokinase disease: Description of a novel activating mutation and contiguous inactivating mutations in human glucokinase (GCK) gene. Molecular endocrinology (Baltimore, Md.) 29 19884385
2014 Elevated CpG island methylation of GCK gene predicts the risk of type 2 diabetes in Chinese males. Gene 28 24992032
2020 Clinical implications of the glucokinase impaired function - GCK MODY today. Physiological research 27 33129248
2011 Berberine regulated Gck, G6pc, Pck1 and Srebp-1c expression and activated AMP-activated protein kinase in primary rat hepatocytes. International journal of biological sciences 27 21647250
2008 Haploinsufficiency at GCK gene is not a frequent event in MODY2 patients. Clinical endocrinology 27 18248649
2008 The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits. Diabetologia 27 19018513
2014 Molecular and clinical characterization of glucokinase maturity-onset diabetes of the young (GCK-MODY) in Japanese patients. Diabetic medicine : a journal of the British Diabetic Association 25 24804978
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
2012 Functional characterization of MODY2 mutations highlights the importance of the fine-tuning of glucokinase and its role in glucose sensing. PloS one 22 22291974
2018 A Hippo Pathway-Related GCK Controls Both Sexual and Vegetative Developmental Processes in the Fungus Sordaria macrospora. Genetics 21 30012560
2015 Aberrant methylation of the GCK gene body is associated with the risk of essential hypertension. Molecular medicine reports 21 25892191
2021 Localized increases in CEPT1 and ATGL elevate plasmalogen phosphatidylcholines in HDLs contributing to atheroprotective lipid profiles in hyperglycemic GCK-MODY. Redox biology 20 33450726
2019 Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia. Journal of diabetes investigation 20 30592380
2015 Circulating ghrelin level is higher in HNF1A-MODY and GCK-MODY than in polygenic forms of diabetes mellitus. Endocrine 20 25987348
2019 Genetic deletion of a short fragment of glucokinase in rabbit by CRISPR/Cas9 leading to hyperglycemia and other typical features seen in MODY-2. Cellular and molecular life sciences : CMLS 19 31720743
2019 Chronic heavy alcohol consumption influences the association between genetic variants of GCK or INSR and the development of diabetes in men: A 12-year follow-up study. Scientific reports 19 31882596
2005 Identification of novel GCK and HNF1A/TCF1 mutations and polymorphisms in German families with maturity-onset diabetes of the young (MODY). Human mutation 19 15841481
2022 Potential impact of GCK, MIR-196A-2 and MIR-423 gene abnormalities on the development and progression of type 2 diabetes mellitus in Asir and Tabuk regions of Saudi Arabia. Molecular medicine reports 18 35293603
2016 GCK gene mutations are a common cause of childhood-onset MODY (maturity-onset diabetes of the young) in Turkey. Clinical endocrinology 18 27256595
2002 GCK and HNF1A mutations in Canadian families with maturity onset diabetes of the young (MODY). Human mutation 18 12442280
2021 Targeting the GCK pathway: a novel and selective therapeutic strategy against RAS-mutated multiple myeloma. Blood 17 33036022
2018 Genetic and clinical characteristics of Chinese children with Glucokinase-maturity-onset diabetes of the young (GCK-MODY). BMC pediatrics 17 29510678
2017 Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families. Clinical genetics 17 28170077
2014 A RARE of hepatic Gck promoter interacts with RARα, HNF4α and COUP-TFII that affect retinoic acid- and insulin-induced Gck expression. The Journal of nutritional biochemistry 17 24973045
2009 GCK is essential to systemic inflammation and pattern recognition receptor signaling to JNK and p38. Proceedings of the National Academy of Sciences of the United States of America 17 19246396
2004 Spectrum of HNF1A and GCK mutations in Canadian families with maturity-onset diabetes of the young (MODY). Clinical and investigative medicine. Medecine clinique et experimentale 17 15305805
1999 Molecular characterisation of plant cDNAs BnMAP4Kalpha1 and BnMAP4Kalpha2 belonging to the GCK/SPS1 subfamily of MAP kinase kinase kinase kinase. Biochimica et biophysica acta 17 9931402
2018 Insights into pathogenesis of five novel GCK mutations identified in Chinese MODY patients. Metabolism: clinical and experimental 16 30257192
2018 Association of Native American ancestry and common variants in ACE, ADIPOR2, MTNR1B, GCK, TCF7L2 and FTO genes with glycemic traits in Colombian population. Gene 15 30063936
2015 Prevalence of Retinopathy in Adult Patients with GCK-MODY and HNF1A-MODY. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 15 26240958
2020 Nanosecond-Timescale Dynamics and Conformational Heterogeneity in Human GCK Regulation and Disease. Biophysical journal 14 32023434
2019 Using Clinical Indices to Distinguish MODY2 (GCK Mutation) and MODY3 (HNF1A Mutation) from Type 1 Diabetes in a Young Chinese Population. Diabetes therapy : research, treatment and education of diabetes and related disorders 14 31214998
2017 Analysis of the GCK gene in 79 MODY type 2 patients: A multicenter Turkish study, mutation profile and description of twenty novel mutations. Gene 14 29056535
2013 Co-inheritance of HNF1a and GCK mutations in a family with maturity-onset diabetes of the young (MODY): implications for genetic testing. Clinical endocrinology 14 23009393
2013 GCK, GCKR polymorphisms and risk of chronic kidney disease in Japanese individuals: data from the J-MICC Study. Journal of nephrology 14 24535998
2012 GCK-MODY diabetes associated with protein misfolding, cellular self-association and degradation. Biochimica et biophysica acta 14 22820548
2021 Evaluation of pregnancy outcomes in women with GCK-MODY. Diabetic medicine : a journal of the British Diabetic Association 13 33277730
2020 Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations. Journal of clinical medicine 13 31968686
2014 Intima-media thickness and endothelial dysfunction in GCK and HNF1A-MODY patients. European journal of endocrinology 13 25501962
2009 Association of polymorphisms of SORBS1, GCK and WISP1 with hypertension in community-dwelling Japanese individuals. Hypertension research : official journal of the Japanese Society of Hypertension 13 19282865
2008 Biochemical characterization of novel glucokinase mutations isolated from Spanish maturity-onset diabetes of the young (MODY2) patients. Journal of human genetics 13 18322640
2014 Mutational analysis of ABCC8, KCNJ11, GLUD1, HNF4A and GCK genes in 30 Chinese patients with congenital hyperinsulinism. Endocrine journal 12 25008049
2013 A report of 2 new cases of MODY2 and review of the literature: implications in the search for type 2 diabetes drugs. Metabolism: clinical and experimental 12 23890519
2011 The coexistence of type 1 diabetes, MODY2 and metabolic syndrome in a young girl. Acta diabetologica 12 21688019
2010 The Caenorhabditis elegans Ste20 kinase, GCK-3, is essential for postembryonic developmental timing and regulates meiotic chromosome segregation. Developmental biology 12 20595048
2009 The germinal center kinase GCK-1 is a negative regulator of MAP kinase activation and apoptosis in the C. elegans germline. PloS one 12 19826475
2021 The novel GCK variant p.Val455Leu associated with hyperinsulinism is susceptible to allosteric activation and is conducive to weight gain and the development of diabetes. Diabetologia 11 34532767
2020 MODY2 in Asia: analysis of GCK mutations and clinical characteristics. Endocrine connections 11 32375122
2017 Dairy Product Consumption Interacts with Glucokinase (GCK) Gene Polymorphisms Associated with Insulin Resistance. Journal of personalized medicine 11 28867816
2013 GCK-MODY diabetes as a protein misfolding disease: the mutation R275C promotes protein misfolding, self-association and cellular degradation. Molecular and cellular endocrinology 11 24001579
2022 Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations. European journal of endocrinology 10 35674212
2021 Functional Inactivation of Drosophila GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2. International journal of molecular sciences 10 33477627
2021 Maturity onset diabetes of the young type 2 (MODY2): Insight from an extended family. Diabetes research and clinical practice 10 33812904
2006 Regulation of the kinase activity of the MIK GCK-like MAP4K by alternative splicing. Plant molecular biology 10 16897489
2005 Clinical characteristics of mutation carriers in a large family with glucokinase diabetes (MODY2). Diabetic medicine : a journal of the British Diabetic Association 10 16026363
2022 Identification and management of GCK-MODY complicating pregnancy in Chinese patients with gestational diabetes. Molecular and cellular biochemistry 9 35229243
2021 Sequencing Cell-free Fetal DNA in Pregnant Women With GCK-MODY. The Journal of clinical endocrinology and metabolism 9 34406393
2019 Association of GCK gene DNA methylation with the risk of clopidogrel resistance in acute coronary syndrome patients. Journal of clinical laboratory analysis 9 31605429

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