Loss of HGF/c-Met signaling in pancreatic β-cells leads to incomplete maternal β-cell adaptation and gestational diabetes mellitus.
Loss of HGF/c-Met signaling in pancreatic β-cells leads to incomplete maternal β-cell adaptation and gestational diabetes mellitus.
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DOI：
10.2337/db11-1154
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发表时间：
2012-05
期刊：
影响因子：
7.7
通讯作者：
García-Ocana A
中科院分区：
文献类型：
--
作者：
Demirci C;Ernst S;Alvarez-Perez JC;Rosa T;Valle S;Shridhar V;Casinelli GP;Alonso LC;Vasavada RC;García-Ocana A
肝细胞生长因子（HGF）是β细胞的有丝分裂原和促胰岛素剂。然而，HGF/c-Met是否在妊娠期母体β细胞适应中起作用尚不清楚。为了解决这个问题，我们研究了胰腺中缺乏c-Met的怀孕小鼠（PancMet KO小鼠）的葡萄糖和β细胞稳态。妊娠小鼠循环HGF、胰岛c-Met及HGF表达增加。重要的是，PancMet KO小鼠在妊娠期（GD）15时表现出β细胞复制减少和β细胞凋亡增加。β细胞复制的减少与胰岛泌乳素受体水平、STAT5核定位和叉头盒M1 mRNA的减少以及p27的上调有关。此外，panmet KO小鼠β-细胞对地塞米松诱导的细胞毒性更敏感，而HGF在体外对地塞米松的细胞毒性有保护作用。这些β细胞增殖和死亡的有害改变导致panmet KO小鼠在GD19和产后早期母体β细胞团扩增不完全。β细胞质量的降低伴随着血糖升高、血浆胰岛素降低和糖耐量的降低。panmet KO小鼠胰岛在妊娠期未能上调GLUT2和胰十二指肠同源盒-1 mRNA、胰岛素含量和葡萄糖刺激的胰岛素分泌。这些研究表明，HGF/c-Met信号对于妊娠期母体β细胞的适应至关重要，其缺失/衰减导致妊娠期糖尿病。
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.
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影响因子：
--
作者：
Friedrichsen, BN;Richter, HE;Moldrup, A
通讯作者：
Moldrup, A
影响因子：
8
作者：
Boney, CM;Verma, A;Vohr, BR
通讯作者：
Vohr, BR
影响因子：
7.7
作者：
García-Ocaña, A;Vasavada, RC;Stewart, AF
通讯作者：
Stewart, AF
影响因子：
10.5
作者：
Gupta, Rana K.;Gao, Nan;Kaestner, Klaus H.
通讯作者：
Kaestner, Klaus H.
DOI：
10.1016/0002-9378(95)90370-4
发表时间：
1995-09-01
影响因子：
9.8
作者：
HORIBE, N;OKAMOTO, T;TOMODA, Y
通讯作者：
TOMODA, Y