Loss of HGF/c-Met Signaling in Pancreatic β-Cells Leads to Incomplete Maternal β-Cell Adaptation and Gestational Diabetes Mellitus
- Cem Demirci1,
- Sara Ernst2,
- Juan C. Alvarez-Perez2,
- Taylor Rosa2,
- Shelley Valle2,
- Varsha Shridhar2,
- Gabriella P. Casinelli2,
- Laura C. Alonso2,
- Rupangi C. Vasavada2 and
- Adolfo García-Ocana2⇓
- 1Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania
- 2Division of Endocrinology and Metabolism Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- Corresponding author: Adolfo Garcia-Ocaña, .
C.D. and S.E. contributed equally to this study.
Hepatocyte growth factor (HGF) is a mitogen and insulinotropic agent for the β-cell. However, whether HGF/c-Met has a role in maternal β-cell adaptation during pregnancy is unknown. To address this issue, we characterized glucose and β-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 β-cell replication and increased β-cell apoptosis at gestational day (GD)15. The decreased β-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 β-cells were more sensitive to dexamethasone-induced cytotoxicity, whereas HGF protected human β-cells against dexamethasone in vitro. These detrimental alterations in β-cell proliferation and death led to incomplete maternal β-cell mass expansion in PancMet KO mice at GD19 and early postpartum periods. The decreased β-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 β-cell adaptation during pregnancy and that its absence/attenuation leads to gestational diabetes mellitus.
- Received August 17, 2011.
- Accepted February 1, 2012.
- © 2012 by the American Diabetes Association.
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