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Cited by 401Pancreatic function and diabetesGenetic Associations and EpidemiologyGlycogen Storage Diseases and Myoclonus

The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver

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Beer, Nicola L., Tribble, Nicholas D., McCulloch, Laura J., Roos, Charlotta, Johnson, Paul R.V., Orho-Melander, Marju, Gloyn, Anna L.·2009·Human Molecular Genetics
DOI 10.1093/hmg/ddp357PMC PMC2758140
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Abstract

Genome-wide association studies have identified a number of signals for both Type 2 Diabetes and related quantitative traits. For the majority of loci, the transition from association signal to mutational mechanism has been difficult to establish. Glucokinase (GCK) regulates glucose storage and disposal in the liver where its activity is regulated by glucokinase regulatory protein (GKRP; gene name GCKR). Fructose-6 and fructose-1 phosphate (F6P and F1P) enhance or reduce GKRP-mediated inhibition, respectively. A common GCKR variant (P446L) is reproducibly associated with triglyceride and fasting plasma glucose levels in the general population. The aim of this study was to determine the mutational mechanism responsible for this genetic association. Recombinant human GCK and both human wild-type (WT) and P446L-GKRP proteins were generated. GCK kinetic activity was observed spectrophotometrically using an NADP(+)-coupled assay. WT and P446L-GKRP-mediated inhibition of GCK activity and subsequent regulation by phosphate esters were determined. Assays matched for GKRP activity demonstrated no difference in dose-dependent inhibition of GCK activity or F1P-mediated regulation. However, the response to physiologically relevant F6P levels was significantly attenuated with P446L-GKRP (n = 18; P <or= 0.03). Experiments using equimolar concentrations of both regulatory proteins confirmed these findings (n = 9; P < 0.001). In conclusion, P446L-GKRP has reduced regulation by physiological concentrations of F6P, resulting indirectly in increased GCK activity. Altered GCK regulation in liver is predicted to enhance glycolytic flux, promoting hepatic glucose metabolism and elevating concentrations of malonyl-CoA, a substrate for de novo lipogenesis, providing a mutational mechanism for the reported association of this variant with raised triglycerides and lower glucose levels.

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  • The liver/lipid cluster includes loci GCKR, PNPLA3, and TM6SF2, which functional experiments have shown to relate to liver lipid metabolism.

    “The liver/lipid cluster includes loci GCKR, PNPLA3, and TM6SF2, which have been shown through functional experiments to relate to liver lipid metabolism (24–31).”

    From Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes (2024) · cites this paper as [27]

    The Results and Discussion (page unavailable) report functional experiments on GCKR and link altered glucokinase regulation to hepatic metabolism and higher triglycerides; the proposed lipogenesis mechanism is a prediction. This paper does not establish the claim about PNPLA3 or TM6SF2, or identify the three loci as a cluster. (LLM, conf=0.88)

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Authors
Beer, N. L., Tribble, N. D., McCulloch, L. J., Roos, C., Johnson, P. R. V., Orho-Melander, M., & Gloyn, A. L.
Affiliations
  • University of Oxford (GB)
  • Lund University (SE)
Corresponding author
Gloyn, Anna L.
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2009-07-30
Volume
18
Issue
21
Pages
4081-4088
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddp357
PMC
PMC2758140
OpenAlex
W2121351699
Cited by
401
References
1
Citations by year
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FWCI
22.15
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Molecular Genetics (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • Oxford University Research Archive (ORA) (University of Oxford) (submittedVersion, cc-by-nc)
Funders
  • European Foundation for the Study of Diabetes
  • Medical Research Council
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
Keywords
GCKR, glucokinase, fasting blood glucose, triglyceride levels, type 2 diabetes, hepatic glucose metabolism, fructose-6-phosphate, fructose-1-phosphate, glycolytic flux, malonyl-CoA, de novo lipogenesis, mutational mechanisms, genetic association
MeSH terms
Blood Glucose, Catalysis, Fasting, Fructosephosphates, Glucokinase, Glucose, Humans, Islets of Langerhans, Kinetics, Liver, Mutation, Recombinant Proteins, Triglycerides, Amino Acid Substitution, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Adaptor Proteins, Signal Transducing

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