Title | Loss of HGF/c-Met signaling in pancreatic β-cells leads to incomplete maternal β-cell adaptation and gestational diabetes mellitus. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Demirci C, Ernst S, Alvarez-Perez JC, Rosa T, Valle S, Shridhar V, Casinelli GP, Alonso LC, Vasavada RC, Garcia-Ocaña A |
Journal | Diabetes |
Volume | 61 |
Issue | 5 |
Pagination | 1143-52 |
Date Published | 2012 May |
ISSN | 1939-327X |
Keywords | Adaptation, Physiological, Animals, Blood Glucose, Cell Death, Cell Proliferation, Diabetes, Gestational, Female, Gene Expression Regulation, Hepatocyte Growth Factor, Homeostasis, Insulin, Insulin-Secreting Cells, Mice, Mice, Knockout, Pregnancy, Proto-Oncogene Proteins c-met, Real-Time Polymerase Chain Reaction, Receptors, Prolactin, Signal Transduction |
Abstract | 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. |
DOI | 10.2337/db11-1154 |
Alternate Journal | Diabetes |
PubMed ID | 22427375 |
PubMed Central ID | PMC3331762 |
Grant List | DK077096 / DK / NIDDK NIH HHS / United States DK067351 / DK / NIDDK NIH HHS / United States DK072264 / DK / NIDDK NIH HHS / United States T32DK07052-32 / DK / NIDDK NIH HHS / United States R01 DK078060 / DK / NIDDK NIH HHS / United States R01 DK072264 / DK / NIDDK NIH HHS / United States R01 DK067351 / DK / NIDDK NIH HHS / United States R01 DK077096 / DK / NIDDK NIH HHS / United States T32 DK007052 / DK / NIDDK NIH HHS / United States |