The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver.
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 disp...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Oxford University Press
2009
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| _version_ | 1797065707024809984 |
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| author | Beer, N Tribble, N McCulloch, L Roos, C Johnson, P Orho-Melander, M Gloyn, A |
| author_facet | Beer, N Tribble, N McCulloch, L Roos, C Johnson, P Orho-Melander, M Gloyn, A |
| author_sort | Beer, N |
| collection | OXFORD |
| description | 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 |
| first_indexed | 2024-03-06T21:32:25Z |
| format | Journal article |
| id | oxford-uuid:451bc29f-1e1f-4c55-940a-e76b11b84d15 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:32:25Z |
| publishDate | 2009 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:451bc29f-1e1f-4c55-940a-e76b11b84d152022-03-26T15:05:54ZThe P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:451bc29f-1e1f-4c55-940a-e76b11b84d15EnglishSymplectic Elements at OxfordOxford University Press2009Beer, NTribble, NMcCulloch, LRoos, CJohnson, POrho-Melander, MGloyn, AGenome-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 |
| spellingShingle | Beer, N Tribble, N McCulloch, L Roos, C Johnson, P Orho-Melander, M Gloyn, A The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. |
| title | The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. |
| title_full | The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. |
| title_fullStr | The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. |
| title_full_unstemmed | The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. |
| title_short | The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. |
| title_sort | 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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