Imperial College London
Alternate

Professor Sir Steve Bloom FMedSci, FRS

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Departmental Academic REF2014 Lead
 
 
 
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Contact

 

+44 (0)20 7594 9048s.bloom Website

 
 
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Assistant

 

Ms Keda Price-Cousins +44 (0)20 7594 9048

 
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Location

 

6N3Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Marzook:2021:10.1016/j.bcp.2021.114656,
author = {Marzook, A and Chen, S and Pickford, P and Lucey, M and Wang, Y and Corrêa, Jr IR and Broichhagen, J and Hodson, DJ and Salem, V and Rutter, GA and Tan, TM and Bloom, SR and Tomas, A and Jones, B},
doi = {10.1016/j.bcp.2021.114656},
journal = {Biochemical Pharmacology},
pages = {1--12},
title = {Evaluation of efficacy- versus affinity-driven agonism with biased GLP-1R ligands P5 and exendin-F1},
url = {http://dx.doi.org/10.1016/j.bcp.2021.114656},
volume = {190},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment of type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in β-arrestin versus G protein coupling show improved metabolic actions in vivo. However, two prototypical G protein-favouring GLP-1R agonists, P5 and exendin-F1, are reported to show divergent effects on insulin secretion. In this study we aimed to resolve this discrepancy by performing a side-by-side characterisation of these two ligands across a variety of in vitro and in vivo assays. Exendin-F1 showed reduced acute efficacy versus P5 for several readouts, including recruitment of mini-G proteins, G protein-coupled receptor kinases (GRKs) and β-arrestin-2. Maximal responses were also lower for both GLP-1R internalisation and the presence of active GLP-1R-mini-Gs complexes in early endosomes with exendin-F1 treatment. In contrast, prolonged insulin secretion in vitro and sustained anti-hyperglycaemic efficacy in mice were both greater with exendin-F1 than with P5. We conclude that the particularly low acute efficacy of exendin-F1 and associated reductions in GLP-1R downregulation appear to be more important than preservation of endosomal signalling to allow sustained insulin secretion responses. This has implications for the ongoing development of affinity- versus efficacy-driven biased GLP-1R agonists as treatments for metabolic disease.
AU  - Marzook,A
AU  - Chen,S
AU  - Pickford,P
AU  - Lucey,M
AU  - Wang,Y
AU  - Corrêa,Jr IR
AU  - Broichhagen,J
AU  - Hodson,DJ
AU  - Salem,V
AU  - Rutter,GA
AU  - Tan,TM
AU  - Bloom,SR
AU  - Tomas,A
AU  - Jones,B
DO  - 10.1016/j.bcp.2021.114656
EP  - 12
PY  - 2021///
SN  - 0006-2952
SP  - 1
TI  - Evaluation of efficacy- versus affinity-driven agonism with biased GLP-1R ligands P5 and exendin-F1
T2  - Biochemical Pharmacology
UR  - http://dx.doi.org/10.1016/j.bcp.2021.114656
UR  - https://www.sciencedirect.com/science/article/pii/S0006295221002690?via%3Dihub
UR  - http://hdl.handle.net/10044/1/89686
VL  - 190
ER  -
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