1. In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist.
- Author
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Jones B, Burade V, Akalestou E, Manchanda Y, Ramchunder Z, Carrat G, Nguyen-Tu MS, Marchetti P, Piemonti L, Leclerc I, Thennati R, Vilsboll T, Thorens B, Tomas A, and Rutter GA
- Subjects
- Adenosine Monophosphate, Animals, Blood Glucose, Cyclic AMP metabolism, HEK293 Cells, Humans, Hypoglycemic Agents pharmacology, Hypoglycemic Agents therapeutic use, Ligands, Mice, Weight Loss, beta-Arrestins metabolism, Glucagon-Like Peptide-1 Receptor Agonists, Diabetes Mellitus, Type 2 drug therapy, Insulins
- Abstract
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., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)
- Published
- 2022
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