title: Glucose transporter-1-deficient mice exhibit impaired development and deformities that are similar to diabetic embryopathy.
abstract: The hyperglycemia of maternal diabetes suppresses the glucose transporter-1 (GLUT1) facilitative glucose transporter 49-66% in preimplantation embryos. Glucose uptake is reduced and apoptosis is activated. We hypothesized that the reduction of embryonic GLUT1 may play a key role in the malformations of diabetic embryopathy. Therefore, we produced GLUT1-deficient transgenic mice [i.e., antisense-GLUT1 (GT1AS)] to determine whether GLUT1 deficiency alone could reproduce the growth defects. Early cell division of fertilized mouse eggs injected with GT1AS was markedly impaired, P < 0.001 vs. controls. Two populations of preimplantation embryos obtained from GT1AS x GT1AS heterozygote matings exhibited reduction of the 2-deoxyglucose uptake rate: one by 50% (presumed heterozygotes, P < 0.001 vs. control) and the other by 95% (presumed homozygotes, P < 0.001 vs. heterozygotes). Embryonic GLUT1 deficiency in the range reported with maternal diabetes was associated with growth retardation and developmental malformations similar to those described in diabetes-exposed embryos: intrauterine growth retardation (31.1%), caudal regression (9.8%), anencephaly with absence of the head (6.6%), microphthalmia (4.9%), and micrognathia (1.6%). Reduced body weight (small embryos, <70% of the nontransgenic body weight) was accompanied by other malformations and a 56% reduction of GLUT1 protein, P < 0.001 vs. nonsmall embryos (body weight >or=70% normal). The heart, brain, and kidneys of embryonic day 18.5 GT1AS embryos exhibited 24-51% reductions of GLUT1 protein. The homozygous GT1AS genotype was lethal during gestation. Reduced embryonic GLUT1 was associated with the appearance of apoptosis. Therefore, GLUT1 deficiency may play a role in producing embryonic malformations resulting from the hyperglycemia of maternal diabetes. Late gestational macrosomia was absent, apparently requiring a different mechanism.
authors.affiliation: Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA. cheilig@jhmi.edu
authors.forename: Charles W
authors.initials: CW
authors.lastname: Heilig
authors.forename: Thomas
authors.initials: T
authors.lastname: Saunders
authors.forename: Frank C
authors.initials: FC
authors.lastname: Brosius
authors.forename: Kelle
authors.initials: K
authors.lastname: Moley
authors.forename: Kathleen
authors.initials: K
authors.lastname: Heilig
authors.forename: Raymond
authors.initials: R
authors.lastname: Baggs
authors.forename: LiRong
authors.initials: L
authors.lastname: Guo
authors.forename: David
authors.initials: D
authors.lastname: Conner
mesh_terms: D000818:Animals; D001692:Biological Transport; D000013:Congenital Abnormalities / Q000235:genetics*; D003433:Crosses, Genetic; D016373:DNA, Antisense / Q000235:genetics; D003847:Deoxyglucose / Q000493:pharmacokinetics; D003920:Diabetes Mellitus / Q000196:embryology* / Q000235:genetics; D005260:Female; D051272:Glucose Transporter Type 1; D008098:Litter Size; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D011247:Pregnancy; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D016373:DNA, Antisense; D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; C495678:Slc2a1 protein, mouse; D003847:Deoxyglucose; D001616:beta-Galactosidase