The therapeutic potential of GLP-1 receptor biased agonism
File(s)
Author(s)
Jones, Benjamin
Type
Journal Article
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists are effective treatments for type 2 diabetes as they stimulate insulin release and promote weight loss through appetite suppression. Their main side effect is nausea. All approved GLP-1 agonists are full agonists across multiple signalling pathways. However, selective engagement with specific intracellular effectors, or biased agonism, has been touted as a means to improve GLP-1 agonists therapeutic efficacy. In this review, I critically examine how GLP-1 receptor-mediated intracellular signalling is linked to physiological responses and discuss the implications of recent studies investigating the metabolic effects of biased GLP-1 agonists. Overall, there is little conclusive evidence that beneficial and adverse effects of GLP-1 agonists are attributable to distinct, nonoverlapping signalling pathways. Instead, G protein-biased GLP-1 agonists appear to achieve enhanced anti-hyperglycaemic efficacy by avoiding GLP-1 receptor desensitisation and downregulation, partly via reduced β-arrestin recruitment. This effect seemingly applies more to insulin release than to appetite regulation and nausea, possible reasons for which are discussed. At present, most evidence derives from cellular and animal studies, and more human data are required to determine whether this approach represents a genuine therapeutic advance.
Date Issued
2022-02-01
Date Acceptance
2021-04-06
Citation
British Journal of Pharmacology, 2022, 179 (4), pp.492-510
ISSN
0007-1188
Publisher
Wiley
Start Page
492
End Page
510
Journal / Book Title
British Journal of Pharmacology
Volume
179
Issue
4
Copyright Statement
© 2021 The Author. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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
Grant Number
RDA05 79560
MR/R010676/1
RDA29
RDC04
N/A
N/A
98102
N/A
Subjects
appetite regulation
biased agonism
glucagon-like peptide-1 receptor
insulin release
β-arrestin
Pharmacology & Pharmacy
1115 Pharmacology and Pharmaceutical Sciences
Publication Status
Published
Date Publish Online
2021-04-20