Endogenous GLP-1 as a key self-defense molecule against lipotoxicity in pancreatic islets.
Int J Mol Med
; 36(1): 173-85, 2015 Jul.
Article
em En
| MEDLINE
| ID: mdl-25976560
ABSTRACT
The number of pro-α cells is known to increase in response to ß cell injury and these cells then generate glucagon-like peptide-1 (GLP-1), thus attenuating the development of diabetes. The aim of the present study was to further examine the role and the mechanisms responsible for intra-islet GLP-1 production as a self-protective response against lipotoxicity. The levels of the key enzyme, prohormone convertase 1/3 (PC1/3), as well as the synthesis and release of GLP-1 in models of lipotoxicity were measured. Furthermore, islet viability, apoptosis, oxidative stress and inflammation, as well as islet structure were assessed after altering GLP-1 receptor signaling. Both prolonged exposure to palmitate and a high-fat diet facilitated PC1/3 expression, as well as the synthesis and release of GLP-1 induced by ß cell injury and the generation of pro-α cells. Prolonged exposure to palmitate increased reactive oxygen species (ROS) production, and the antioxidant, N-acetylcysteine (NAC), partially prevented the detrimental effects induced by palmitate on ß cells, resulting in decreased GLP-1 levels. Furthermore, the inhibition of GLP-1 receptor (GLP-1R) signaling by treatment with exendin(9-39) further decreased cell viability, increased cell apoptosis and caused a stronger inhibition of the ß cell-specific transcription factor, pancreatic duodenal homeobox 1 (PDX1). Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of ß cell marker expression. Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression. Overall, our data demonstrate that an increase in the number of pro-α cells and the activation of the intra-islet GLP-1 system comprise a self-defense mechanism for enhancing ß cell survival to combat lipid overload, which is in part mediated by oxidative stress and inflammation.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Palmitatos
/
Células Secretoras de Glucagon
/
Células Secretoras de Insulina
/
Peptídeo 1 Semelhante ao Glucagon
/
Dieta Hiperlipídica
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Int J Mol Med
Ano de publicação:
2015
Tipo de documento:
Article