Evidence map›Paper›PMID 19643913›Full record

ArticleHuman molecular genetics2009

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

Nicola L Beer, Nicholas D Tribble, Laura J McCulloch, Charlotta Roos, Paul R V Johnson, Marju Orho-Melander, Anna L Gloyn

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Human molecular genetics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 251 papers, 14 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
251citing papers in PubMed, 14 pooled it
20.6field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

251 citing papers in PubMed, 14 syntheses or guidelines pooled it, 389 citations in OpenAlex.

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191 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 3 institutions in 2 countries.

Nicola L BeerOxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.
Nicholas D Tribble
Laura J McCulloch
Charlotta Roos
Paul R V Johnson
Marju Orho-Melander
Anna L Gloyn
University of Oxford · GBLund University · SEOxford Centre for Diabetes, Endocrinology and Metabolism · GB

Funding

Medical Research Council 81696Medical Research Council G0700222Medical Research Council G0700222(81696)
6 · The paper itself

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.

Indexed as

Adaptor Proteins, Signal TransducingAmino Acid SubstitutionBlood GlucoseCatalysisFastingFructosephosphatesGene Expression ProfilingGlucokinaseGlucoseHumansIslets of LangerhansKineticsLiverMutationRecombinant ProteinsReverse Transcriptase Polymerase Chain ReactionAdaptor Proteins, Signal TransducingBlood Glucosefructose-1-phosphatefructose-6-phosphateFructosephosphatesGCKR protein, humanGlucokinaseGlucoseRecombinant ProteinsTriglycerides

Identifiers

PMID19643913
PMCPMC2758140
OpenAlexW2121351699

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.