Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 1 de 1
Filtrar
Más filtros




Base de datos
Asunto de la revista
Intervalo de año de publicación
1.
Pharmacol Res ; 176: 106058, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34995796

RESUMEN

The intestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are key regulators of postprandial bone turnover in humans. We hypothesized that GIP and GLP-2 co-administration would provide stronger effect on bone turnover than administration of the hormones separately, and tested this using subcutaneous injections of GIP and GLP-2 alone or in combination in humans. Guided by these findings, we designed series of GIPR-GLP-2R co-agonists as template for new osteoporosis treatment. The clinical experiment was a randomized cross-over design including 10 healthy men administered subcutaneous injections of GIP and GLP-2 alone or in combination. The GIPR-GLP-2R co-agonists were characterized in terms of binding and activation profiles on human and rodent GIP and GLP-2 receptors, and their pharmacokinetic (PK) profiles were improved by dipeptidyl peptidase-4 protection and site-directed lipidation. Co-administration of GIP and GLP-2 in humans resulted in an additive reduction in bone resorption superior to each hormone individually. The GIPR-GLP-2R co-agonists, designed by combining regions of importance for cognate receptor activation, obtained similar efficacies as the two native hormones and nanomolar potencies on both human receptors. The PK-improved co-agonists maintained receptor activity along with their prolonged half-lives. Finally, we found that the GIPR-GLP-2R co-agonists optimized toward the human receptors for bone remodeling are not feasible for use in rodent models. The successful development of potent and efficacious GIPR-GLP-2R co-agonists, combined with the improved effect on bone metabolism in humans by co-administration, support these co-agonists as a future osteoporosis treatment.


Asunto(s)
Remodelación Ósea/efectos de los fármacos , Polipéptido Inhibidor Gástrico/farmacología , Péptido 2 Similar al Glucagón/farmacología , Receptor del Péptido 2 Similar al Glucagón/agonistas , Receptores de la Hormona Gastrointestinal/agonistas , Adulto , Animales , Células COS , Chlorocebus aethiops , Estudios Cruzados , Femenino , Polipéptido Inhibidor Gástrico/sangre , Polipéptido Inhibidor Gástrico/farmacocinética , Péptido 2 Similar al Glucagón/sangre , Péptido 2 Similar al Glucagón/farmacocinética , Receptor del Péptido 2 Similar al Glucagón/genética , Humanos , Masculino , Ratones Endogámicos C57BL , Osteoporosis/tratamiento farmacológico , Receptores de la Hormona Gastrointestinal/genética , Método Simple Ciego , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA