In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist.
Diabetes Obes Metab
; 24(11): 2090-2101, 2022 11.
Article
en En
| MEDLINE
| ID: mdl-35676825
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 ANDMETHODS:
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 ß-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.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Diabetes Mellitus Tipo 2
/
Insulinas
Límite:
Animals
/
Humans
Idioma:
En
Año:
2022
Tipo del documento:
Article