Imperial College London
Alternate

ProfessorTriciaTan

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Chair in Metabolic Medicine and Endocrinology
 
 
 
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Contact

 

+44 (0)20 3313 8038t.tan

 
 
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Location

 

6N6ECommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Hinds:2024:10.1111/dom.15288,
author = {Hinds, CE and Peace, E and Chen, S and Davies, I and El, Eid L and Tomas, A and Tan, T and Minnion, J and Jones, B and Bloom, SR},
doi = {10.1111/dom.15288},
journal = {Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics},
pages = {65--77},
title = {Abolishing β-arrestin recruitment is necessary for the full metabolic benefits of G protein-biased glucagon-like peptide-1 receptor agonists},
url = {http://dx.doi.org/10.1111/dom.15288},
volume = {26},
year = {2024}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - AimEarlier studies have shown that peptide glucagon-like peptide-1 receptor (GLP-1R) agonists with reduced β-arrestin recruitment show enhanced anti-hyperglycaemic efficacy through avoidance of GLP-1R desensitization. However, the ligand modifications needed to decrease β-arrestin recruitment usually also reduces GLP-1R affinity, therefore higher doses are needed. Here we aimed to develop new, long-acting, G protein-biased GLP-1R agonists with acute signalling potency comparable with semaglutide, to provide insights into specific experimental and therapeutic scenarios.Materials and MethodsNew GLP-1R agonist peptides were assessed using a variety of in vitro and in vivo assays.ResultsFirst, we show that very substantial reductions in β-arrestin recruitment efficacy are required to realize fully the benefits of GLP-1R agonism on blood glucose lowering in mice, with more moderate reductions being less effective. Secondly, our lead compound (SRB107) performs substantially better than semaglutide for effects on blood glucose and weight loss, which may be jointly attributable to its biased agonist action and protracted pharmacokinetics. Thirdly, we show that biased agonist-specific GLP-1R internalization profiles occur at clinically relevant pharmacological concentrations. Finally, we show that SRB107 cAMP signalling is differentially modulated by single and double GLP1R coding variants seen in human populations, with implications for GLP-1R agonist pharmacogenomics.ConclusionsCompletely abolishing β-arrestin recruitment improves the anti-hyperglycaemic effects of GLP-1R agonists in mice.
AU  - Hinds,CE
AU  - Peace,E
AU  - Chen,S
AU  - Davies,I
AU  - El,Eid L
AU  - Tomas,A
AU  - Tan,T
AU  - Minnion,J
AU  - Jones,B
AU  - Bloom,SR
DO  - 10.1111/dom.15288
EP  - 77
PY  - 2024///
SN  - 1462-8902
SP  - 65
TI  - Abolishing β-arrestin recruitment is necessary for the full metabolic benefits of G protein-biased glucagon-like peptide-1 receptor agonists
T2  - Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics
UR  - http://dx.doi.org/10.1111/dom.15288
UR  - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:001075497900001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
UR  - https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15288
UR  - http://hdl.handle.net/10044/1/107841
VL  - 26
ER  -
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