RESUMEN
The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) whose activation results in suppression of food intake and improvement of glucose metabolism. Several receptor interacting proteins regulate the signaling of GLP-1R such as G protein-coupled receptor kinases (GRK) and ß-arrestins. Here we evaluated the physiological and pharmacological impact of GRK inhibition on GLP-1R activity leveraging small molecule inhibitors of GRK2 and GRK3. We demonstrated that inhibition of GRK: i) inhibited GLP-1-mediated ß-arrestin recruitment, ii) enhanced GLP-1-induced insulin secretion in isolated islets and iii) has additive effect with dipeptidyl peptidase 4 in mediating suppression of glucose excursion in mice. These findings highlight the importance of GRK to modulate GLP-1R function in vitro and in vivo. GRK inhibition is a potential therapeutic approach to enhance endogenous and pharmacologically stimulated GLP-1R signaling.
Asunto(s)
Quinasa 1 del Receptor Acoplado a Proteína-G/antagonistas & inhibidores , Péptido 1 Similar al Glucagón/metabolismo , Amidas/química , Animales , Células CHO , Calcio/metabolismo , Cricetulus , Diabetes Mellitus/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Ingestión de Alimentos , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Glucosa/metabolismo , Humanos , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Ratones , Obesidad/metabolismo , Fosforilación , Receptores de Glucagón/metabolismo , Insuficiencia Renal Crónica/metabolismo , Transducción de Señal , beta-Arrestinas/metabolismoRESUMEN
Hypothalamic hamartomas are benign tumors known to cause gelastic or dacrystic seizures, precocious puberty, developmental delay, and medically refractory epilepsy. These tumors are most often sporadic but rarely can be associated with Pallister-Hall syndrome, an autosomal dominant familial syndrome caused by truncation of glioblastoma transcription factor 3, a downstream effector in the sonic hedgehog pathway. In this clinical report, the authors describe two brothers with a different familial syndrome. To the best of the authors' knowledge, this is the first report in the literature describing a familial syndrome caused by germline mutations in the Smoothened (SMO) gene and the first familial syndrome associated with hypothalamic hamartomas other than Pallister-Hall syndrome. The authors discuss the endoscopic endonasal biopsy and subtotal resection of a large hypothalamic hamartoma in one of the patients as well as the histopathological findings encountered. Integral to this discussion is the understanding of the hedgehog pathway; therefore, the underpinnings of this pathway and its clinical associations to date are also reviewed.