Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist

Phil Pickford, Maria Lucey, Roxana-Maria Rujan, Emma Rose McGlone, Stavroula Bitsi, Fiona B. Ashford, Jr Ivan R. Corrêa, David J. Hodson, Alejandra Tomas, Giuseppe Deganutti, Christopher A. Reynolds, Bryn M. Owen, Tricia M. Tan, James Minnion, Ben Jones, Stephen R. Bloom

    Research output: Contribution to journalArticlepeer-review

    3 Citations (Scopus)
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    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.
    Original languageEnglish
    Article number101242
    JournalMolecular Metabolism
    Volume51
    Early online date30 Apr 2021
    DOIs
    Publication statusPublished - Sep 2021

    Bibliographical note

    This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

    Keywords

    • GLP-1
    • glucagon
    • oxyntomodulin
    • biased agonism
    • partial agonism
    • β-arrestin
    • Glucagon
    • Biased agonism
    • Partial agonism
    • Oxyntomodulin

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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