Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2021-09-01
Date Acceptance
2021-04-22
Citation
Molecular Metabolism, 2021, 51
ISSN
2212-8778
Publisher
Elsevier
Journal / Book Title
Molecular Metabolism
Volume
51
Copyright Statement
Ó2021 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
License URL
Sponsor
Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
The Academy of Medical Sciences
Society for Endocrinology
European Foundation for the Study of Diabetes
British Society for Neuroendocrinology
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33933675
PII: S2212-8778(21)00087-9
Grant Number
RDA05 79560
MR/R010676/1
RDA29
RDC04
N/A
N/A
98102
N/A
Subjects
GLP-1
biased agonism
glucagon
oxyntomodulin
partial agonism
β-arrestin
Publication Status
Published
Coverage Spatial
Germany
Article Number
ARTN 101242
Date Publish Online
2021-04-30