Expression of the gene encoding the high-Km glucose transporter 2 by the early postimplantation mouse embryo is essential for neural tube defects associated with diabetic embryopathy.
OBJECTIVE
Excess glucose transport to embryos during diabetic pregnancy causes congenital malformations. The early postimplantation embryo expresses the gene encoding the high-Km GLUT2 (also known as SLC2A2) glucose transporter. The hypothesis tested here is that high-Km glucose transport by GLUT2 causes malformations resulting from maternal hyperglycaemia during diabetic pregnancy.


METHODS
Glut2 mRNA was assayed by RT-PCR. The Km of embryo glucose transport was determined by measuring 0.5-20 mmol/l 2-deoxy[3H]glucose transport. To test whether the GLUT2 transporter is required for neural tube defects resulting from maternal hyperglycaemia, Glut2+/- mice were crossed and transient hyperglycaemia was induced by glucose injection on day 7.5 of pregnancy. Embryos were recovered on day 10.5, and the incidence of neural tube defects in wild-type, Glut2+/- and Glut2-/- embryos was scored.


RESULTS
Early postimplantation embryos expressed Glut2, and expression was unaffected by maternal diabetes. Moreover, glucose transport by these embryos showed Michaelis-Menten kinetics of 16.19 mmol/l, consistent with transport mediated by GLUT2. In pregnancies made hyperglycaemic on day 7.5, neural tube defects were significantly increased in wild-type embryos, but Glut2+/- embryos were partially protected from neural tube defects, and Glut2-/- embryos were completely protected from these defects. The frequency of occurrence of wild-type, Glut2+/- and Glut2-/- embryos suggests that the presence of Glut2 alleles confers a survival advantage in embryos before day 10.5.


CONCLUSIONS
High-Km glucose transport by the GLUT2 glucose transporter during organogenesis is responsible for the embryopathic effects of maternal diabetes.
Li
R
R
Developmental and Stem Cell Biology, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215, USA.
Thorens
B
B
Loeken
M R
MR
D000818:Animals; D001692:Biological Transport; D003433:Crosses, Genetic; D003847:Deoxyglucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics*; D047108:Embryonic Development; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051273:Glucose Transporter Type 2 / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D009436:Neural Tube Defects / Q000235:genetics*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051273:Glucose Transporter Type 2; D012333:RNA, Messenger; D003847:Deoxyglucose