In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist
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Aims: To describe the in vitro characteristics and antidiabetic in vivo efficacy of the novel glucagon-like peptide-1 receptor agonist (GLP-1RA) GL0034. Materials and Methods: Glucagon-like peptide-1 receptor (GLP-1R) kinetic binding parameters, cyclic adenosine monophosphate (cAMP) signalling, endocytosis and recycling were measured using HEK293 and INS-1832/3 cells expressing human GLP-1R. Insulin secretion was measured in vitro using INS-1832/3 cells, mouse islets and human islets. Chronic administration studies to evaluate weight loss and glycaemic effects were performed in db/db and diet-induced obese mice. Results: Compared to the leading GLP-1RA semaglutide, GL0034 showed increased binding affinity and potency-driven bias in favour of cAMP over GLP-1R endocytosis and β-arrestin-2 recruitment. Insulin secretory responses were similar for both ligands. GL0034 (6 nmol/kg) led to at least as much weight loss and lowering of blood glucose as did semaglutide at a higher dose (14 nmol/kg). Conclusions: GL0034 is a G protein-biased agonist that shows powerful antidiabetic effects in mice, and may serve as a promising new GLP-1RA for obese patients with type 2 diabetes.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Diabetes, Obesity and Metabolism |
| Vol/bind | 24 |
| Udgave nummer | 11 |
| Sider (fra-til) | 2090-2101 |
| Antal sider | 12 |
| ISSN | 1462-8902 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
This study was funded by a grant from Sun Pharmaceuticals Inc and others. Funding information
Funding Information:
This study was funded by a grant from Sun Pharmaceuticals Inc. to Guy A. Rutter and Alejandra Tomas. Guy A. Rutter was also supported by a Wellcome Trust Investigator (WT212625/Z/18/Z) Award, an MRC Program grant (MR/R022259/1) and a John R. Evans Leaders Award from Innovation Canada and Alejandra Tomas, Ben Jones and Guy A. Rutter by MRC Project Grant (MR/R010676/1). This project has received funding from the European Union's Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115881 (RHAPSODY) to Guy A. Rutter and Bernard Thorens. Alejandra Tomas also acknowledges funding from Diabetes UK, the European Federation for the Study of Diabetes, the Commonwealth, the Integrated Biological Imaging Network, and the Lilly Research Award Program. Ben Jones has received funding from the Imperial Post‐doctoral Post‐CCT Research Fellowship scheme, the European Federation for the Study of Diabetes, the Academy of Medical Sciences, the Society for Endocrinology, the British Society for Neuroendocrinology, the Engineering and Physical Sciences Research Council and the Lilly Research Award Program. Provision of human islets from Milan was supported by JDRF award 31‐2008‐416 (ECIT Islet for Basic Research program). We thank Professor Kevin Murphy (Imperial College) for assistance with animal husbandry.
Publisher Copyright:
© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
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