| First Author | Demirci C | Year | 2012 |
| Journal | Diabetes | Volume | 61 |
| Issue | 5 | Pages | 1143-52 |
| PubMed ID | 22427375 | Mgi Jnum | J:196854 |
| Mgi Id | MGI:5490015 | Doi | 10.2337/db11-1154 |
| Citation | Demirci C, et al. (2012) Loss of HGF/c-Met signaling in pancreatic beta-cells leads to incomplete maternal beta-cell adaptation and gestational diabetes mellitus. Diabetes 61(5):1143-52 |
| abstractText | 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 upregulation 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. |
