The role of small molecule GPR119 agonist, AS1535907, in glucose-stimulated insulin secretion and pancreatic ß-cell function.
Diabetes Obes Metab
; 13(1): 34-41, 2011 Jan.
Article
em En
| MEDLINE
| ID: mdl-21114601
ABSTRACT
AIM:
AS1535907, a small molecule agonist of GPR119, was assessed for its glucose-stimulated insulin secretory activity and pancreatic ß-cell function in type 2 diabetes.METHODS:
Both in vitro and in vivo tests were conducted using NIT-1 and HEK293 cell lines, male normal and db/db mice and isolated perfused rat pancreas preparations.RESULTS:
AS1535907 had an EC50 value of 1.5 µM for human GPR119 transfected in HEK293 cells. AS1535907 enhanced insulin secretion in NIT-1 cells and in the perfused rat pancreas. A transient increase in the human insulin promoter activity was also observed in NIT-1 cells. First-phase insulin secretion was particularly more evident in the AS1535907-treated perfused rat pancreas than that in the nateglinide or glibenclamide-treated group. Oral glucose tolerance improved following a single dose of AS1535907 in normal and db/db mice. Subsequently, 2 weeks of multiple dosing significantly increased plasma insulin levels and decreased blood glucose levels in db/db mice. After 3 weeks of treatment in db/db mice, the numbers of insulin and proliferation cell nuclear antigen-positive cells and the islet area were significantly higher than those in the vehicle-treated mice. As compared with the vehicle, gene expression analysis revealed that AS1535907 significantly upregulated transcription factors (Nkx 2.2, Nkx 6.1, NeuroD and activin A), responsible for ß-cell regulation and prohormone-converting enzyme 1 responsible for insulin biosynthesis.CONCLUSION:
These results suggest that AS1535907 can potentially regulate first-phase insulin secretion and exert a protective effect on pancreatic ß-cell function via regulation of transcription factors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pâncreas
/
Piridinas
/
Óxidos N-Cíclicos
/
Receptores Acoplados a Proteínas G
/
Diabetes Mellitus Tipo 2
/
Células Secretoras de Insulina
/
Hipoglicemiantes
Limite:
Animals
Idioma:
En
Revista:
Diabetes Obes Metab
Assunto da revista:
ENDOCRINOLOGIA
/
METABOLISMO
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Japão