PMID- 22427375
OWN - NLM
STAT- MEDLINE
DCOM- 20120628
LR  - 20211021
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 61
IP  - 5
DP  - 2012 May
TI  - Loss of HGF/c-Met signaling in pancreatic beta-cells leads to incomplete maternal 
      beta-cell adaptation and gestational diabetes mellitus.
PG  - 1143-52
LID - 10.2337/db11-1154 [doi]
AB  - 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.
FAU - Demirci, Cem
AU  - Demirci C
AD  - Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, 
      USA.
FAU - Ernst, Sara
AU  - Ernst S
FAU - Alvarez-Perez, Juan C
AU  - Alvarez-Perez JC
FAU - Rosa, Taylor
AU  - Rosa T
FAU - Valle, Shelley
AU  - Valle S
FAU - Shridhar, Varsha
AU  - Shridhar V
FAU - Casinelli, Gabriella P
AU  - Casinelli GP
FAU - Alonso, Laura C
AU  - Alonso LC
FAU - Vasavada, Rupangi C
AU  - Vasavada RC
FAU - Garcia-Ocana, Adolfo
AU  - Garcia-Ocana A
LA  - eng
GR  - DK077096/DK/NIDDK NIH HHS/United States
GR  - DK067351/DK/NIDDK NIH HHS/United States
GR  - DK072264/DK/NIDDK NIH HHS/United States
GR  - T32DK07052-32/DK/NIDDK NIH HHS/United States
GR  - R01 DK078060/DK/NIDDK NIH HHS/United States
GR  - R01 DK072264/DK/NIDDK NIH HHS/United States
GR  - R01 DK067351/DK/NIDDK NIH HHS/United States
GR  - R01 DK077096/DK/NIDDK NIH HHS/United States
GR  - T32 DK007052/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120316
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Blood Glucose)
RN  - 0 (Insulin)
RN  - 0 (Receptors, Prolactin)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Adaptation, Physiological
MH  - Animals
MH  - Blood Glucose/physiology
MH  - Cell Death
MH  - Cell Proliferation
MH  - Diabetes, Gestational/*etiology/metabolism
MH  - Female
MH  - Gene Expression Regulation/physiology
MH  - Hepatocyte Growth Factor/genetics/*metabolism
MH  - Homeostasis
MH  - Insulin/blood
MH  - Insulin-Secreting Cells/cytology/*physiology
MH  - Mice
MH  - Mice, Knockout
MH  - Pregnancy
MH  - Proto-Oncogene Proteins c-met/genetics/*metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Receptors, Prolactin/genetics/metabolism
MH  - Signal Transduction
PMC - PMC3331762
EDAT- 2012/03/20 06:00
MHDA- 2012/06/29 06:00
PMCR- 2013/05/01
CRDT- 2012/03/20 06:00
PHST- 2012/03/20 06:00 [entrez]
PHST- 2012/03/20 06:00 [pubmed]
PHST- 2012/06/29 06:00 [medline]
PHST- 2013/05/01 00:00 [pmc-release]
AID - db11-1154 [pii]
AID - 1154 [pii]
AID - 10.2337/db11-1154 [doi]
PST - ppublish
SO  - Diabetes. 2012 May;61(5):1143-52. doi: 10.2337/db11-1154. Epub 2012 Mar 16.