Diabetes Obes Metab. 2022 Jun 8. doi: 10.1111/dom.14794. Online ahead of print.
In vivo and in vitro characterisation of GL0034, a novel long-acting GLP-1 receptor agonist
Ben Jones 1, Vinod Burade 2, Elina Akalestou 3, Yusman Manchanda 3, Zenouska Ramchunder 3, Gaëlle Carrat 3, Marie-Sophie Nguyen-Tu 3, Piero Marchetti 4, Lorenzo Piemonti 5, Isabelle Leclerc 3 6, Thennati Rajamannar 2, Tina Vilsboll 7, Bernard Thorens 8, Alejandra Tomas 3, Guy A Rutter 3 9 6
Aims: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective treatments for type 2 diabetes (T2D). Here, we describe the in vitro characteristics and anti-diabetic in vivo efficacy of the novel GLP-1RA GL0034.
Materials and methods: GLP-1R kinetic binding parameters, cAMP signalling, endocytosis and recycling were measured using HEK293 and INS-1 832/3 cells expressing human GLP-1R. Insulin secretion was measured in vitro using INS-1 832/3 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 anti-diabetic effects in mice, and may serve as a promising new GLP-1RA for obese patients with T2D. This article is protected by copyright. All rights reserved.
- PMID: 35676825
- DOI: 10.1111/dom.14794