Glucose transporter isoform-3 mutations cause early pregnancy loss and fetal growth restriction
Glucose transporter isoform-3 mutations cause early pregnancy loss and fetal growth restriction
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DOI：
10.1152/ajpendo.00344.2006
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发表时间：
2007-05-01
影响因子：
5.1
通讯作者：
Devaskar, Sherin U.
中科院分区：
文献类型：
--
作者：
Ganguly, Amit;McKnight, Robert A.;Devaskar, Sherin U.
葡萄糖转运蛋白亚型3（GLUT 3）是滋养层促进葡萄糖转运蛋白。为了研究这种亚型在胚胎发育中的作用，我们创建了一种新的GLUT 3-null小鼠，并观察到当两个等位基因突变时，早期胚胎发育和神经胚形成阶段的损失被阻止。尽管存在其他相关的同种型，特别是GLUT 1，这种损失还是发生了。相反，当单个等位基因发生突变时，尽管胚胎细胞凋亡增加，但植入前胚胎中GLUT 3和GLUT 1亚细胞定位的适应性变化导致植入后存活。这种存活率受到GLUT 3介导的经胎盘葡萄糖转运减少的影响，导致妊娠晚期胎儿生长受限。这产生了年轻的男性和女性成年人表现出追赶性生长，具有正常的基础葡萄糖、胰岛素、胰岛素样生长因子-I和IGF-结合蛋白-3浓度、脂肪和瘦体重以及葡萄糖和胰岛素耐受性。我们的结论是，GLUT 3突变导致基因剂量依赖性早孕丢失或妊娠晚期胎儿生长受限，尽管存在胚胎和胎盘GLUT 1和系统A氨基酸胎盘运输的补偿性增加。GLUT 3在胚胎发育中维持生命的关键功能作用为研究妊娠早期具有类似后果的人类GLUT 3突变的存在提供了基础。
Glucose transporter isoform-3 (GLUT3) is the trophoblastic facilitative glucose transporter. To investigate the role of this isoform in embryonic development, we created a novel GLUT3-null mouse and observed arrested early embryonic development and loss at neurulation stage when both alleles were mutated. This loss occurred despite the presence of other related isoforms, particularly GLUT1. In contrast, when a single allele was mutated, despite increased embryonic cell apoptosis, adaptive changes in the subcellular localization of GLUT3 and GLUT1 in the preimplantation embryo led to postimplantation survival. This survival was compromised by decreased GLUT3-mediated transplacental glucose transport, causing late-gestation fetal growth restriction. This yielded young male and female adults demonstrating catch-up growth, with normal basal glucose, insulin, insulin-like growth factor-I and IGF-binding protein-3 concentrations, fat and lean mass, and glucose and insulin tolerance. We conclude that GLUT3 mutations cause a gene dose-dependent early pregnancy loss or late-gestation fetal growth restriction despite the presence of embryonic and placental GLUT1 and a compensatory increase in system A amino acid placental transport. This critical life-sustaining functional role for GLUT3 in embryonic development provides the basis for investigating the existence of human GLUT3 mutations with similar consequences during early pregnancy.