Diabetes in pregnancy is associated with a number of perinatal problems such as macrosomia and neonatal hypoglycemia. There is also evidence suggesting that diabetes or even impaired glucose tolerance during pregnancy may be risk factors for the development of diabetes in the offspring. It is clear that the perinatal consequences of gestational diabetes are not simply a function of maternal hyperglycemia, since macrosomic infants are frequently born to mothers whose diabetes is well controlled. Preliminary research suggests that there are increases in the expression and activity of GLUT1 glucose transporters in the syncytial basal membrane of placental tissue from women whose diabetes is adequately controlled. Thus there appear to be continuing perturbations in a system intimately involved in fetal growth and development. It is hypothesized that elevated fetal glucose, resulting from maternal fetal hyperglycemia, causes, through stimulation of fetal growth factors, increased fetoplacental growth including increased expression of the basal membrane GLUT1 glucose transporter, the rate-limiting barrier to placental glucose transport. The resultant increase in transplacental glucose flux prolongs fetal hyperglycemia and leads to continued derangement of the fetal growth axis, despite normalization of maternal plasma glucose. This project is designed to explore this hypothesis by investigating the expression and activity of the human placental GLUT1 glucose transporter in diabetic pregnancies.
Aim number 1 : To characterize the changes in placental glucose transporter expression and activity in diabetic pregnancy and to correlate these parameters with measures of maternal glycemic status and fetal growth factors.
Aim number 2 : To assess the functional consequences of changes in glucose transporter expression and activity for the placental transfer of glucose.
Aim number 3 : To establish the mechanisms responsible for the changes in glucose transporter expression and activity through transcriptional and posttranscriptional modulation and through short term regulatory events.
Aim number 4 : To examine the mechanisms governing the (re)distribution of transporters between microvillous and basal membranes. The information obtained from these experimental approaches will significantly advance our understanding of the fetal response to maternal diabetes and the factors generating adverse perinatal consequences.
| Baumann, Marc U; Zamudio, Stacy; Illsley, Nicholas P (2007) Hypoxic upregulation of glucose transporters in BeWo choriocarcinoma cells is mediated by hypoxia-inducible factor-1. Am J Physiol Cell Physiol 293:C477-85 |
| Baumann, Marc U; Deborde, Sylvie; Illsley, Nicholas P (2002) Placental glucose transfer and fetal growth. Endocrine 19:13-22 |
| Ebenbichler, C F; Kaser, S; Laimer, M et al. (2002) Polar expression and phosphorylation of human leptin receptor isoforms in paired, syncytial, microvillous and basal membranes from human term placenta. Placenta 23:516-21 |
| Vardhana, Pratibhasri A; Illsley, Nicholas P (2002) Transepithelial glucose transport and metabolism in BeWo choriocarcinoma cells. Placenta 23:653-60 |
| Illsley, N P (2000) Placental glucose transport in diabetic pregnancy. Clin Obstet Gynecol 43:116-26 |
