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{Pickford:2021:10.1016/j.molmet.2021.101242,
author = {Pickford, P and Lucey, M and Rujan, R-M and McGlone, ER and Bitsi, S and Ashford, FB and Corrêa, IR and Hodson, DJ and Tomas, A and Deganutti, G and Reynolds, CA and Owen, BM and Tan, TM and Minnion, J and Jones, B and Bloom, SR},
doi = {10.1016/j.molmet.2021.101242},
journal = {Molecular Metabolism},
title = {Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist},
url = {http://dx.doi.org/10.1016/j.molmet.2021.101242},
volume = {51},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - OBJECTIVE: Glucagon-like peptide-1 and glucagon receptor (GLP-1R/GCGR) co-agonism can maximise weight loss and improve glycaemic control in type 2 diabetes and obesity. In this study we investigated the cellular and metabolic effects of modulating the balance between G protein and β-arrestin-2 recruitment at GLP-1R and GCGR using oxyntomodulin (OXM)-derived co-agonists. This strategy has been previously shown to improve the duration of action of GLP-1R mono-agonists by reducing target desensitisation and downregulation. METHODS: Dipeptidyl dipeptidase-4 (DPP-4)-resistant OXM analogues were generated and assessed for a variety of cellular readouts. Molecular dynamic simulations were used to gain insights into the molecular interactions involved. In vivo studies were performed in mice to identify effects on glucose homeostasis and weight loss. RESULTS: Ligand-specific reductions in β-arrestin-2 recruitment were associated with slower GLP-1R internalisation and prolonged glucose-lowering action in vivo. The putative benefits of GCGR agonism were retained, with equivalent weight loss compared to the GLP-1R mono-agonist liraglutide in spite of a lesser degree of food intake suppression. The compounds tested showed only a minor degree of biased agonism between G protein and β-arrestin-2 recruitment at both receptors and were best classified as partial agonists for the two pathways measured. CONCLUSIONS: Diminishing β-arrestin-2 recruitment may be an effective way to increase the therapeutic efficacy of GLP-1R/GCGR co-agonists. These benefits can be achieved by partial rather than biased agonism.
AU  - Pickford,P
AU  - Lucey,M
AU  - Rujan,R-M
AU  - McGlone,ER
AU  - Bitsi,S
AU  - Ashford,FB
AU  - Corrêa,IR
AU  - Hodson,DJ
AU  - Tomas,A
AU  - Deganutti,G
AU  - Reynolds,CA
AU  - Owen,BM
AU  - Tan,TM
AU  - Minnion,J
AU  - Jones,B
AU  - Bloom,SR
DO  - 10.1016/j.molmet.2021.101242
PY  - 2021///
SN  - 2212-8778
TI  - Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist
T2  - Molecular Metabolism
UR  - http://dx.doi.org/10.1016/j.molmet.2021.101242
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33933675
UR  - https://www.sciencedirect.com/science/article/pii/S2212877821000879?via%3Dihub
UR  - http://hdl.handle.net/10044/1/88387
VL  - 51
ER  -
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