Compromised chronic efficacy of a glucokinase activator AZD1656 in mouse models for common human GCKR variants.

Autor: Ford BE; Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK., Chachra SS; Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK., Alshawi A; Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Medical Laboratory Technique Department, Kufa Institute, Al-Furat Al-Awsat Technical University, Kufa, Iraq., Oakley F; Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK., Fairclough RJ; Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Smith DM; Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Tiniakos D; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Dept of Pathology, Aretaieion Hospital Medical School, National and Kapodistrian University of Athens, Greece., Agius L; Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: Loranne.agius@ncl.ac.uk.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2024 Nov; Vol. 229, pp. 116499. Date of Electronic Publication: 2024 Aug 20.
DOI: 10.1016/j.bcp.2024.116499
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: B.E.F., S.S.C., A.A., D.T., L.A. declare no competing interests relevant to this study. R.J.F., D.M.S. are employees and shareholders of AstraZeneca. F.O. is a director, shareholder and employee of Fibrofind limited Fibrofind IP limited.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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