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 ؋ 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 >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.embryo ͉ antisense ͉ transgenic ͉ development ͉ apoptosis

A novel microdeletion in 1(p34.2p34.3), involving the SLC2A1 (GLUT1) gene, and severe delayed development

“…14 Transgenic mice with isolated GLUT1 suppression display reduced glucose uptake and developmental malformations, including intrauterine growth impairment, anencephaly, microphthalmia, and caudal regression syndrome similar to diabetic embryopathy. 15 Metabolic screening in our patient identified an abnormal ratio of CSF glucose to blood glucose, which is consistent with GLUT1 deficiency syndrome. A high-fat, low-carbohydrate (ketogenic) diet can effectively control the seizures and the complex motor disorder in GLUT1 deficiency syndrome but has little effect on the cognitive impairment.…”

Will the original glucose transporter isoform please stand up!

“…Initially, GLUT1-deficient transgenic mice were produced using antisense-GLUT1 constructs. In preimplantation embryos obtained from these mice, glucose uptake was reduced compared with wild-type mice (51). In addition, homozygous GLUT1 mutant mouse embryos obtained from the antisense-GLUT1 transgenic mouse mating revealed severely impaired organogenesis consisting of caudal regression, agenesis of kidneys, stunted growth, absent head, microphthalmia, and other malformations reminiscent of the human infant of a hyperglycemic diabetic mother (51).…”

GLUT1 enhances mTOR activity independently of TSC2 and AMPK

“…HEK293 cells were obtained from American Type Culture Collection (Manassas, VA). Rat glomerular mesangial cell (MC) lines were developed by Dr. Charles Heilig (University of Florida) and have been previously characterized by our groups (11,13,14). The MC lines were grown in RPMI, 20% NuSerum IV and G418.…”