Loss of HGF/c-Met signaling in pancreatic ß-cells leads to incomplete maternal ß-cell adaptation and gestational diabetes mellitus.
Diabetes
; 61(5): 1143-52, 2012 May.
Article
em En
| MEDLINE
| ID: mdl-22427375
ABSTRACT
Hepatocyte growth factor (HGF) is a mitogen and insulinotropic agent for the ß-cell. However, whether HGF/c-Met has a role in maternal ß-cell adaptation during pregnancy is unknown. To address this issue, we characterized glucose and ß-cell homeostasis in pregnant mice lacking c-Met in the pancreas (PancMet KO mice). Circulating HGF and islet c-Met and HGF expression were increased in pregnant mice. Importantly, PancMet KO mice displayed decreased ß-cell replication and increased ß-cell apoptosis at gestational day (GD)15. The decreased ß-cell replication was associated with reductions in islet prolactin receptor levels, STAT5 nuclear localization and forkhead box M1 mRNA, and upregulation of p27. Furthermore, PancMet KO mouse ß-cells were more sensitive to dexamethasone-induced cytotoxicity, whereas HGF protected human ß-cells against dexamethasone in vitro. These detrimental alterations in ß-cell proliferation and death led to incomplete maternal ß-cell mass expansion in PancMet KO mice at GD19 and early postpartum periods. The decreased ß-cell mass was accompanied by increased blood glucose, decreased plasma insulin, and impaired glucose tolerance. PancMet KO mouse islets failed to upregulate GLUT2 and pancreatic duodenal homeobox-1 mRNA, insulin content, and glucose-stimulated insulin secretion during gestation. These studies indicate that HGF/c-Met signaling is essential for maternal ß-cell adaptation during pregnancy and that its absence/attenuation leads to gestational diabetes mellitus.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Diabetes Gestacional
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Fator de Crescimento de Hepatócito
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Proteínas Proto-Oncogênicas c-met
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Células Secretoras de Insulina
Limite:
Animals
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Pregnancy
Idioma:
En
Revista:
Diabetes
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos