Journal
BIOCHEMICAL PHARMACOLOGY
Volume 190, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114656
Keywords
GLP-1R; Biased agonism; Endocytosis; Exendin-4; beta-arrestin
Categories
Funding
- MRC [MR/R010676/1, MR/N00275X/1, MR/S025618/1, MR/R022259/1, MR/L02036X/1]
- BBSRC
- NIHR
- NIHR Biomedical Research Centre Funding Scheme
- Diabetes UK [17/0005681]
- Academy of Medical Sciences
- British Society for Neuroendocrinology
- European Federation for the Study of Diabetes
- EPSRC
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [715884]
- Wellcome Trust [212625/Z/18/Z]
- EU/EFPIA/Innovative Medicines Initiative 2 Joint Undertaking (RHAPSODY) [115881]
- Diabetes UK Harry Keen Fellowship
- Society for Endocrinology
- Medical Research Council [MR/N00275X/1, MR/S025618/1] Funding Source: researchfish
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In this study, differences between the GLP-1R agonists P5 and exendin-F1 were examined through various assays, revealing that while exendin-F1 showed lower acute efficacy, it demonstrated greater effects on insulin secretion and sustained anti-hyperglycaemic efficacy in mice compared to P5.
The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment of type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in beta-arrestin versus G protein coupling show improved metabolic actions in vivo. However, two prototypical G protein-favouring GLP-1R agonists, P5 and exendin-F1, are reported to show divergent effects on insulin secretion. In this study we aimed to resolve this discrepancy by performing a side-by-side characterisation of these two ligands across a variety of in vitro and in vivo assays. Exendin-F1 showed reduced acute efficacy versus P5 for several readouts, including recruitment of mini-G proteins, G protein-coupled receptor kinases (GRKs) and beta-arrestin-2. Maximal responses were also lower for both GLP-1R internalisation and the presence of active GLP-1R-mini-Gs complexes in early endosomes with exendin-F1 treatment. In contrast, prolonged insulin secretion in vitro and sustained anti-hyperglycaemic efficacy in mice were both greater with exendin-F1 than with P5. We conclude that the particularly low acute efficacy of exendin-F1 and associated reductions in GLP-1R downregulation appear to be more important than preservation of endosomal signalling to allow sustained insulin secretion responses. This has implications for the ongoing development of affinity- versus efficacy-driven biased GLP-1R agonists as treatments for metabolic disease.
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