Glucose transporter isoform-3 mutations cause early pregnancy loss and fetal growth restriction

Amit Ganguly, Robert A. McKnight, Santanu Raychaudhuri, Bo Chul Shin, Zhigui Ma, Kelle Moley, Sherin U. Devaskar

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)E1241-E1255
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume292
Issue number5
DOIs
StatePublished - May 2007

Keywords

  • Development
  • Preimplantation embryo
  • Transplacental glucose transport

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