FETAL CIRCULATORY ADJUSTMENT IN DIABETIC PREGNANCY

妊娠并发糖尿病控制不佳的后代 胎儿宫内发育迟缓和早产， 系统性围产期葡萄糖稳态的扰动可能不利地 影响中枢神经系统（CNS）环境，使新生儿易患 CNS损伤。 这一建议的论点是，系统性低血糖和 高血糖导致循环、代谢和血脑屏障 渗透性变化，这可能会使胎儿和新生儿处于更高的风险 用于缺氧缺血性损伤和/或其它CNS损伤。 的具体目标 该建议研究（1）前列腺素类，（6-酮- 前列腺素F1 α、血栓素B2和PGE 2）对围产期CNS的影响 在改变的全身血糖状态期间的循环和代谢，（2） 低血糖对缺血性CNS损伤发展的重要性， (3)高血糖对缺血性CNS发展的重要性 高血糖对血脑屏障的影响 妊娠早期和晚期胎儿的渗透性，剖腹产 递送的表面活性剂处理的早产绵羊，并将这些发现与 高血糖的足月绵羊。 研究将在长期插管的绵羊胎儿中进行， 新生儿输注胰岛素诱导低血糖，葡萄糖诱导 用于正血糖高胰岛素钳夹的高血糖、胰岛素和葡萄糖 而安慰剂用于对照胎儿。 胎儿中枢神经系统血流量 （总量和区域）将用放射性核素标记的 微球，脑代谢的菲克原则，在稳态- 状态条件下，通过动脉-上矢状窦差异 适当的代谢物和血脑屏障通透性（总的和 区域性）通过放射性标记示踪剂（24 Na， 14 C-蔗糖和3 H-甘露醇）进入脑内。 病理生理变化将是 通过比较低血糖或高血糖的结果来确定 胎羊与对照组、安慰剂输注组、胎羊。 这个项目的总体目标是 建议是阐明CNS病理生理学相关的 全身葡萄糖稳态紊乱。

In offspring of pregnancies complicated by poorly controlled diabetes mellitus, intrauterine growth retardation and premature delivery, perturbations in systemic perinatal glucose homeostasis may adversely affect the central nervous system (CNS) milieu, predisposing the neonate to CNS injury. The thesis of this proposal is that systemic hypoglycemia and hyperglycemia result in circulatory, metabolic, and blood-brain barrier permeability changes, which may place the fetus and neonate at higher risk for hypoxic-ischemic injury, and/or other CNS injury. The specific aims of this proposal examine (1) the importance of prostanoids, (6-keto- prostaglandin F1alpha, thromboxane B2 and PGE2) to perinatal CNS circulation and metabolism during altered systemic glycemic states, (2) the importance of hypoglycemia to the development of ischemic CNS injury and (3) the importance of hyperglycemia to the development of ischemic CNS injury and (4) the effects of hyperglycemia on blood-brain barrier permeability in the early and late gestation fetus, cesarean-section delivered surfactant treated premature sheep and compare these findings to that of hyperglycemic full-term sheep. Studies will be performed in the chronically catheterized ovine fetus and neonate infused with insulin to induce hypoglycemia, glucose to induce hyperglycemia, insulin and glucose for a euglycemic hyperinsulinemic clamp and placebo for control fetuses. Fetal central nervous system blood flow (total and regional) will be measured with radionuclide-labelled microspheres, cerebral metabolism by the Fick principle, during steady- state conditions, by arterial-superior sagittal sinus differences of appropriate metabolites and blood-brain barrier permeability (total and regional) by the uni-directional influx of radiolabelled tracers (24Na, 14C-sucrose and 3H-mannitol) into brain. Pathophysiologic changes will be identified by comparing the results in the hypoglycemic or hyperglycemic fetuses to control, placebo-infused, fetal sheep. The overall goal of this proposal is to elucidate the CNS pathophysiology associated with perturbations in systemic glucose homeostasis.