Glucose transport and metabolism are critical for mammalian blastocyst formation and further development. We have previously shown that any decrease in glucose transport, basal or insulin-stimulated, results in enhanced apoptosis at this stage which manifests later in pregnancy as a malformation or miscarriage. In preliminary studies, we have cloned a novel, insulin-regulated glucose transporter, GLUT8, which is expressed at high levels in the blastocyst stage in the mouse. Unlike the other glucose transporters, GLUT8 is localized intracellularly; however, upon insulin-treatment is translocated to the plasma membrane. This movement corresponds to an increase in glucose uptake. Also in preliminary studies, we have discovered that GLUT8 affects blastocyst survival. A decrease in GLUT8 expression by antisense oligonucleotides leads to an increase in apoptosis at the blastocyst stage as detected by TUNEL assay. These antisense embryos when transferred back to foster mice experience a higher rate of pregnancy failure and resorption compared to sense treated embryos. Thus, we hypothesize that the mammalian blastocyst represents the earliest insulin-regulated tissue and responds to insulin or IGF-l by translocation of GLUT8. We further postulate that establishment of this distinct glucose transport system is crucial for this stage of development. Dysregulation of this transport system may be responsible for increased apoptosis experienced under conditions of hyperinsulinemia as seen in polycystic ovary syndrome, and thus for the increased rate of pregnancy losses experienced by these women. The three aims to be pursued are: 1. Where is GLUT8 located intracellularly and in which cell type is GLUT8 expressed in the mammalian blastocyst? 2. How does IGF-1/insulin stimulate GLUT8 translocation and glucose uptake and how does this compare to GLUT4 translocation in skeletal muscle and adipocytes? 3. What is the physiological role of GLUT8 and how does decreased expression of this protein induce apoptosis at the blastocyst stage? Can triggering of GLUT8 translocation rescue the blastocyst from hyperinsulinemic conditions? Upon completion of the proposed research, we expect to have determined the location, mechanism and function of this novel glucose transporter expressed predominantly at the blastocyst stage. The role of this transporter in pathologic conditions and the ability to manipulate this transport system to improve embryo development and pregnancy outcome will be elucidated. Thus, these results are ultimately expected to have a significant impact on the field of reproductive biology.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Tasca, Richard J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Obstetrics & Gynecology
Schools of Medicine
Saint Louis
United States
Zip Code
DeBosch, Brian J; Kluth, Oliver; Fujiwara, Hideji et al. (2014) Early-onset metabolic syndrome in mice lacking the intestinal uric acid transporter SLC2A9. Nat Commun 5:4642
Debosch, Brian J; Chen, Zhouji; Saben, Jessica L et al. (2014) Glucose transporter 8 (GLUT8) mediates fructose-induced de novo lipogenesis and macrosteatosis. J Biol Chem 289:10989-98
Bibee, Kristin P; Augustin, Robert; Gazit, Vered et al. (2013) The apical sorting signal for human GLUT9b resides in the N-terminus. Mol Cell Biochem 376:163-73
DeBosch, Brian J; Chen, Zhouji; Finck, Brian N et al. (2013) Glucose transporter-8 (GLUT8) mediates glucose intolerance and dyslipidemia in high-fructose diet-fed male mice. Mol Endocrinol 27:1887-96
Grindler, Natalia M; Moley, Kelle H (2013) Maternal obesity, infertility and mitochondrial dysfunction: potential mechanisms emerging from mouse model systems. Mol Hum Reprod 19:486-94
Schoeller, Erica L; Albanna, Gabriella; Frolova, Antonina I et al. (2012) Insulin rescues impaired spermatogenesis via the hypothalamic-pituitary-gonadal axis in Akita diabetic mice and restores male fertility. Diabetes 61:1869-78
Schoeller, Erica L; Schon, Samantha; Moley, Kelle H (2012) The effects of type 1 diabetes on the hypothalamic, pituitary and testes axis. Cell Tissue Res 349:839-47
DeBosch, Brian J; Chi, Maggie; Moley, Kelle H (2012) Glucose transporter 8 (GLUT8) regulates enterocyte fructose transport and global mammalian fructose utilization. Endocrinology 153:4181-91
Wang, Qiang; Chi, Maggie M; Schedl, Tim et al. (2012) An intercellular pathway for glucose transport into mouse oocytes. Am J Physiol Endocrinol Metab 302:E1511-8
Luzzo, Kerri M; Wang, Qiang; Purcell, Scott H et al. (2012) High fat diet induced developmental defects in the mouse: oocyte meiotic aneuploidy and fetal growth retardation/brain defects. PLoS One 7:e49217

Showing the most recent 10 out of 44 publications