title: Loss of HGF/c-Met signaling in pancreatic β-cells leads to incomplete maternal β-cell adaptation and gestational diabetes mellitus.
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.
authors.affiliation: Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Cem
authors.initials: C
authors.lastname: Demirci
authors.forename: Sara
authors.initials: S
authors.lastname: Ernst
authors.forename: Juan C
authors.initials: JC
authors.lastname: Alvarez-Perez
authors.forename: Taylor
authors.initials: T
authors.lastname: Rosa
authors.forename: Shelley
authors.initials: S
authors.lastname: Valle
authors.forename: Varsha
authors.initials: V
authors.lastname: Shridhar
authors.forename: Gabriella P
authors.initials: GP
authors.lastname: Casinelli
authors.forename: Laura C
authors.initials: LC
authors.lastname: Alonso
authors.forename: Rupangi C
authors.initials: RC
authors.lastname: Vasavada
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Ocana
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001786:Blood Glucose / Q000502:physiology; D016923:Cell Death; D049109:Cell Proliferation; D016640:Diabetes, Gestational / Q000209:etiology* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D007328:Insulin; D011981:Receptors, Prolactin; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met