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

doi:10.1016/j.molmet.2021.101242

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 journal › Article › peer-review

13 Citations (Scopus)

118 Downloads (Pure)

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 language	English
Article number	101242
Number of pages	18
Journal	Molecular Metabolism
Volume	51
Early online date	30 Apr 2021
DOIs	https://doi.org/10.1016/j.molmet.2021.101242
Publication status	Published - Sept 2021

Bibliographical note

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

Funding

The Section of Endocrinology and Investigative Medicine is funded by grants from the MRC, BBSRC, and NIHR and is supported by the NIHR Biomedical Research Centre Funding Scheme. The views expressed are those of the authors and not necessarily those of the funders. D.J.H. was supported by MRC (MR/N00275X/1 and MR/S025618/1) and Diabetes UK (17/0005681) project grants. This project received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (Starting Grant 715,884 to D.J.H.). A.T. acknowledges funding from Diabetes UK. B.J. acknowledges support from the Academy of Medical Sciences, Society for Endocrinology, British Society for Neuroendocrinology, and an EPSRC capital award. B.J. and A.T. also received funding from the MRC (MR/R010676/1) and the European Federation for the Study of Diabetes. E.R.M. acknowledges support from Royal College of Surgeons of England and MRC clinical research training fellowships. B.J. has received grant funding from Sun Pharmaceuticals.

Funders	Funder number
Academy of Medical Sciences
Society for Endocrinology
Medical Research Council
Biotechnology and Biological Sciences Research Council
National Institute for Health and Care Research
British Society for Neuroendocrinology
European Federation for the Study of Diabetes
Royal College of Surgeons of England
Sun Pharmaceuticals
European Research Council
Horizon Europe
NIHR Manchester Biomedical Research Centre	MR/S025618/1
Engineering and Physical Sciences Research Council	MR/R010676/1
Diabetes UK	17/0005681
UK Research and Innovation	MR/N00275X/1
Horizon Europe	715884

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.molmet.2021.101242Licence: CC BY

PublishedFinal published version, 3.04 MBLicence: CC BY

Cite this

Pickford, P., Lucey, M., Rujan, R.-M., McGlone, E. R., Bitsi, S., Ashford, F. B., Ivan R. Corrêa, J., Hodson, D. J., Tomas, A., Deganutti, G., Reynolds, C. A., Owen, B. M., Tan, T. M., Minnion, J., Jones, B., & Bloom, S. R. (2021). Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist. Molecular Metabolism, 51, Article 101242. https://doi.org/10.1016/j.molmet.2021.101242

Pickford, P, Lucey, M, Rujan, R-M, McGlone, ER, Bitsi, S, Ashford, FB, Ivan R. Corrêa, J, Hodson, DJ, Tomas, A, Deganutti, G , Reynolds, CA, Owen, BM, Tan, TM, Minnion, J, Jones, B & Bloom, SR 2021, 'Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist', Molecular Metabolism, vol. 51, 101242. https://doi.org/10.1016/j.molmet.2021.101242

@article{9ac47fdf16494b82b500da8279b9cd88,

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

abstract = "ObjectiveGlucagon-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.MethodsDipeptidyl 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.ResultsLigand-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.ConclusionsDiminishing 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.",

keywords = "GLP-1, glucagon, oxyntomodulin, biased agonism, partial agonism, β-arrestin, Glucagon, Biased agonism, Partial agonism, Oxyntomodulin",

author = "Phil Pickford and Maria Lucey and Roxana-Maria Rujan and McGlone, {Emma Rose} and Stavroula Bitsi and Ashford, {Fiona B.} and {Ivan R. Corr{\^e}a}, Jr and Hodson, {David J.} and Alejandra Tomas and Giuseppe Deganutti and Reynolds, {Christopher A.} and Owen, {Bryn M.} and Tan, {Tricia M.} and James Minnion and Ben Jones and Bloom, {Stephen R.}",

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

year = "2021",

month = sep,

doi = "10.1016/j.molmet.2021.101242",

language = "English",

volume = "51",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier",

}

TY - JOUR

T1 - Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist

AU - Pickford, Phil

AU - Lucey, Maria

AU - Rujan, Roxana-Maria

AU - McGlone, Emma Rose

AU - Bitsi, Stavroula

AU - Ashford, Fiona B.

AU - Ivan R. Corrêa, Jr

AU - Hodson, David J.

AU - Tomas, Alejandra

AU - Deganutti, Giuseppe

AU - Reynolds, Christopher A.

AU - Owen, Bryn M.

AU - Tan, Tricia M.

AU - Minnion, James

AU - Jones, Ben

AU - Bloom, Stephen R.

N1 - This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

PY - 2021/9

Y1 - 2021/9

N2 - ObjectiveGlucagon-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.MethodsDipeptidyl 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.ResultsLigand-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.ConclusionsDiminishing 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.

AB - ObjectiveGlucagon-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.MethodsDipeptidyl 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.ResultsLigand-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.ConclusionsDiminishing 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.

KW - GLP-1

KW - glucagon

KW - oxyntomodulin

KW - biased agonism

KW - partial agonism

KW - β-arrestin

KW - Glucagon

KW - Biased agonism

KW - Partial agonism

KW - Oxyntomodulin

UR - http://www.scopus.com/inward/record.url?scp=85106948402&partnerID=8YFLogxK

U2 - 10.1016/j.molmet.2021.101242

DO - 10.1016/j.molmet.2021.101242

M3 - Article

SN - 2212-8778

VL - 51

JO - Molecular Metabolism

JF - Molecular Metabolism

M1 - 101242

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this