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

• Published in: American journal of physiology: endocrinology and metabolism 2007-05, Vol.292 (5), p.E1241-E1255
• Main Authors: Ganguly, Amit, McKnight, Robert A, Raychaudhuri, Santanu, Shin, Bo-Chul, Ma, Zhigui, Moley, Kelle, Devaskar, Sherin U
• Format: Article
• Language: English
• Subjects: Abortion, Spontaneous - genetics; Animals; Animals, Newborn; Blastocyst - metabolism; Blastocyst - physiology; Blood Glucose - metabolism; Body Composition - physiology; Embryonic Development - genetics; Embryonic Stem Cells - metabolism; Embryonic Stem Cells - physiology; Female; Fetuses; Genes; Genetics; Glucose; Glucose Tolerance Test; Glucose Transporter Type 3 - deficiency; Glucose Transporter Type 3 - genetics; Glucose Transporter Type 3 - metabolism; Immunohistochemistry; Insulin - blood; Insulin-Like Growth Factor Binding Protein 3 - blood; Insulin-Like Growth Factor I - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Placenta - anatomy & histology; Placenta - metabolism; Placenta - physiology; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00344.2006

1 Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California; and 2 Department of Obstetrics and Gynecology, Cell Biology, and Physiology, Washington University School of Medicine, St. Louis, Missouri Submitted 13 July 2006 ; accepted in final form 1 January 2007 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. preimplantation embryo; transplacental glucose transport; development Address for reprint requests and other correspondence: S. U. Devaskar, Dept. of Pediatrics, David Geffen School of Medicine, 10833 Le Conte Ave., MDCC-B2-375, Los Angeles, CA 90095 (e-mail: sdevaskar{at}mednet.ucla.edu )