PLACENTAL GLUCOSE TRANSPORT IN DIABETIC PREGNANCIES

妊娠期糖尿病与许多围产期问题有关，如巨大儿和新生儿低血糖。也有证据表明，怀孕期间糖尿病甚至糖耐量受损可能是后代患糖尿病的危险因素。显然，妊娠期糖尿病的围产期后果不仅仅是母亲高血糖的功能，因为糖尿病得到很好控制的母亲生下的巨大儿往往是如此。初步研究表明，糖尿病得到充分控制的女性胎盘组织合体基底膜中GLUT1葡萄糖转运体的表达和活性增加。因此，在一个与胎儿生长发育密切相关的系统中，似乎存在持续的扰动。据推测，由母体胎儿高血糖引起的胎儿血糖升高，通过胎儿生长因子的刺激，导致胎儿胎盘生长增加，包括胎盘葡萄糖转运的限速屏障--基底膜GLUT1葡萄糖转运体的表达增加。由此导致的经胎盘葡萄糖流量的增加延长了胎儿的高血糖，并导致胎儿生长轴的持续紊乱，尽管母亲的血糖正常化。该项目旨在通过研究人胎盘GLUT1葡萄糖转运体在糖尿病妊娠中的表达和活性来探索这一假说。目的1：研究糖尿病妊娠胎盘葡萄糖转运蛋白表达和活性的变化，并探讨其与母体血糖水平和胎儿生长因子的关系。目的2：评估葡萄糖转运蛋白表达和活性改变对胎盘葡萄糖转运的功能影响。目的3：建立通过转录和转录后调控以及短期调控事件导致葡萄糖转运蛋白表达和活性变化的机制。目的4：研究微绒毛和基底膜之间转运蛋白(再)分布的机制。从这些实验方法中获得的信息将极大地促进我们对胎儿对母亲糖尿病的反应以及产生不良围产期后果的因素的理解。

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.