In:
Diabetes, Obesity and Metabolism, Wiley, Vol. 24, No. 11 ( 2022-11), p. 2090-2101
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1462-8902
,
1463-1326
Language:
English
Publisher:
Wiley
Publication Date:
2022
detail.hit.zdb_id:
2004918-3