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Lookup NU author(s): Dr Brian FordORCiD, Dr Shruti Chachra, Ahmed Alshawi, Professor Fiona OakleyORCiD, Professor Dina Tiniakos, Professor Loranne Agius
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Glucokinase activators (GKAs) have been developed as blood glucose lowering drugs for type 2 diabetes. Despite good short-term efficacy, several GKAs showed a decline in efficacy chronically during clinical trials. The underlying mechanisms remain incompletely understood. We tested the hypothesis that deficiency in the liver glucokinase regulatory protein (GKRP) as occurs with common human GCKR variants affects chronic GKA efficacy. We used a Gckr-P446L mouse model for the GCKR exonic rs1260326 (P446L) variant and the Gckr-del/wt mouse to model transcriptional deficiency to test for chronic efficacy of the GKA, AZD1656 in GKRP-deficient states. In the Gckr-P446L mouse, the blood glucose lowering efficacy of AZD1656 (3 mg/kg body wt) after 2 weeks was independent of genotype. However after 19 weeks, efficacy was maintained in wild-type but declined in the LL genotype, in conjunction with raised hepatic glucokinase activity and without raised liver lipids. Sustained blood glucose lowering efficacy in wild-type mice was associated with qualitatively similar but more modest changes in the liver transcriptome compared with the P446L genotype, consistent with GKA therapy representing a more modest glucokinase excess than the P446L genotype. Chronic treatment with AZD1656 in the Gckr-del/wt mouse was associated with raised liver triglyceride and hepatocyte microvesicular steatosis. The results show that in mouse models of liver GKRP deficiency in conjunction with functional liver glucokinase excess as occurs in association with common human GCKR variants, GKRP-deficiency predisposes to declining efficacy of the GKA in lowering blood glucose and to GKA induced elevation in liver lipids.
Author(s): Ford BE, Chachra SS, Alshawi A, Oakley F, Fairclough RJ, Smith DM, Tiniakos D, Agius L
Publication type: Article
Publication status: Published
Journal: Biochemical Pharmacology
Year: 2024
Volume: 229
Print publication date: 01/11/2024
Online publication date: 20/08/2024
Acceptance date: 19/08/2024
Date deposited: 04/09/2024
ISSN (print): 0006-2952
ISSN (electronic): 1873-2968
Publisher: Elsevier
URL: https://doi.org/10.1016/j.bcp.2024.116499
DOI: 10.1016/j.bcp.2024.116499
Data Access Statement: RNA-seq data was deposited in the NCBI Gene Expression Omnibus (GEO) database under accession series GSE228698. Raw figure data is deposited at data.ncl under the collection 7065890. Individual figure DOIs are: Figure-1. 10.25405/data.ncl.25189130. Figure-2. 10.25405/data.ncl.25189199. Figure-3. 10.25405/data.ncl.25189169. Figure-4. 10.25405/data.ncl.25189181. Figure-5. 10.25405/data.ncl.25189187. Figure-6. 10.25405/data.ncl.25189193. Figure-7. 10.25405/data.ncl.25189196. Figure-8. 10.25405/data.ncl.25189208.
PubMed id: 39173844
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