In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist

Ben Jones, Vinod Burade, Elina Akalestou, Yusman Manchanda, Zenouska Ramchunder, Gaëlle Carrat, Marie-Sophie Nguyen-Tu, Piero Marchetti, Lorenzo Piemonti, Isabelle Leclerc, Thennati Rajamannar, Tina Vilsboll, Bernard Thorens, Alejandra Tomas, Guy A Rutter

Abstrakt

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.

OriginalsprogEngelsk
TidsskriftDiabetes, Obesity and Metabolism
Vol/bind24
Udgave nummer11
Sider (fra-til)2090-2101
Antal sider12
ISSN1462-8902
DOI
StatusUdgivet - nov. 2022

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