Journal
DIABETES
Volume 61, Issue 5, Pages 1143-1152Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db11-1154
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Funding
- American Diabetes Association [1-10-BS-59]
- National Institutes of Health (NIH) [DK067351, DK077096, DK072264]
- Lawson Wilkins Pediatric Endocrine Society
- NIH [T32DK07052-32]
- NIH/National Center for Research Resources
- National Institute of Diabetes and Digestive and Kidney Diseases
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Hepatocyte growth factor (HGF) is a mitogen and insulinotropic agent for the beta-cell. However, whether HGF/c-Met has a role in maternal beta-cell adaptation during pregnancy is unknown. To address this issue, we characterized glucose and beta-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 beta-cell replication and increased beta-cell apoptosis at gestational day (GD)15. The decreased beta-cell replication was associated with reductions in islet prolactin receptor levels, STAT5 nuclear localization and forkhead box M1 mRNA, and up-regulation of p27. Furthermore, PancMet KO mouse beta-cells were more sensitive to dexamethasone-induced cytotoxicity, whereas HGF protected human beta-cells against dexamethasone in vitro. These detrimental alterations in beta-cell proliferation and death led to incomplete maternal beta-cell mass expansion in PancMet KO mice at GD19 and early postpartum periods. The decreased beta-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 beta-cell adaptation during pregnancy and that its absence/attenuation leads to gestational diabetes mellitus. Diabetes 61:1143-1152, 2012
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