FETAL CIRCULATORY ADJUSTMENT IN DIABETIC PREGNANCY

妊娠合并糖尿病控制不佳的后代 糖尿病、宫内发育迟缓和早产， 全身性围产期血糖稳态紊乱可能会对 影响中枢神经系统(CNS)环境，使新生儿容易患上 中枢神经系统损伤。这项建议的主题是全身性低血糖和 高血糖导致循环、代谢和血脑屏障 通透性改变，这可能会使胎儿和新生儿面临更高的风险 适用于缺氧缺血性损伤和/或其他中枢神经系统损伤。的具体目标 这项建议审查(1)前列腺素的重要性，(6-酮- 前列腺素F1α、血栓素B2和前列腺素E_2)对围产期中枢神经系统的影响 全身性血糖状态改变时的循环和代谢，(2) 低血糖在缺血性中枢神经系统损伤和发展中的重要性 (3)高血糖在缺血性中枢神经系统发展中的重要性 (4)高血糖对血脑屏障的影响 早孕、晚孕、剖宫产胎儿的通透性 经表面活性物质处理的早产羊，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和 新生儿输注胰岛素诱导低血糖，葡萄糖诱导 正常血糖高胰岛素钳夹的高血糖、高胰岛素和高血糖 对照组胎儿服用安慰剂。胎儿中枢神经系统血流 (总量和区域)将用放射性核素标记进行测量 微球，大脑代谢根据菲克原理，在稳定的- 状态条件，由动脉-上矢状窦的差异 适当的代谢物和血脑屏障通透性(总和 区域)通过放射性标记示踪剂(24Na， ~(14)C-蔗糖和~3H-甘露醇)注入脑内。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 胎儿要控制，注入安慰剂的胎羊。这个项目的总体目标是 建议阐明与以下相关的中枢神经系统病理生理学 全身葡萄糖动态平衡的紊乱。

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.