Effect of Gestational Diabetes on Placental Development

总结 在正常妊娠期间，母体胰岛素敏感性在妊娠中期和晚期下降， 葡萄糖输送到胎儿，而母体β细胞质量和胰岛素分泌显着增加。在 妊娠糖尿病（GDM），胰岛素抵抗和需求之间存在不匹配，导致葡萄糖 不容忍在一些患者中，特别是那些肥胖的患者，过度的胰岛素抵抗导致这种不匹配， 而在其他患者中，特别是瘦女性，胰岛素缺乏是主要原因。有必要 用于研究这些患者中GDM的不同原因。拟议项目将利用 由急性高脂肪喂养引起的小鼠模型，类似于瘦女性的GDM;它们是葡萄糖不耐受的 仅在怀孕期间，胰岛素抵抗，但β细胞增殖失败，胰岛素分泌减少。 初步表明，饮食特异性干扰胎盘刺激的β细胞增殖。 来自GDM妇女的大量胎盘组织学数据显示，胎盘绒毛成熟和 血管生成在足月时被破坏。此外，与胎盘中血管生成相关的基因以及与 在小鼠模型中，胰岛中对胎盘信号的反应性在近期被破坏。综合这些 研究结果表明，妊娠期糖尿病患者的胎盘功能受到破坏， 母婴健康。拟议项目的目的1是在整个研究期间对配对的胎盘-胰岛样本进行分析。 正常妊娠和GDM并发症小鼠的妊娠过程，以确定中断 到胎盘-β细胞的交叉通讯。目的2将检查妊娠早期胎盘血管生成， 在小鼠模型中以及通过使用超声在患有GDM的女性中，这些研究将 显示胎盘的改变是否先于葡萄糖耐受不良的发生，并可能导致 GDM的病理生理学。

SUMMARY During a normal pregnancy, maternal insulin sensitivity declines in the second and third trimester to allow glucose delivery to the fetus, while maternal beta cell mass and insulin secretion dramatically increase. In gestational diabetes (GDM), there is a mismatch between insulin resistance and demand, resulting in glucose intolerance. In some patients, particular those who are obese, excess insulin resistance drives this mismatch, whereas in other patients, particularly lean women, insulin deficiency is the main contributor. There is a need for research that addresses the distinct causes of GDM in these patients. The proposed project will utilize a mouse model caused by acute high fat feeding that resembles GDM in lean women; they are glucose intolerant only during pregnancy, insulin resistant, but with failed beta cell proliferation and reduced insulin secretion. Preliminary show that the diet specifically interferes with placentally-stimulated beta cell proliferation. Extensive placental histological data from women with GDM show that placental villous maturation and angiogenesis are disrupted at term. Furthermore, genes associated with angiogenesis in the placenta and with responsiveness to placental signals in the islet are disrupted near term in the mouse model. Together these findings suggest that placental function is disrupted in GDM, in ways that contribute to the effects on both maternal and infant health. Aim 1 of the proposed project is to profile paired placental-islet samples over the course of gestation in normal pregnancies, and those complicated by GDM in the mouse to identify disruptions to placenta-beta cell cross-communication. Aim 2 will examine placental angiogenesis in early pregnancy and at term in both the mouse model and, by using ultrasound, in women with GDM. Together, these studies will show whether alterations in the placenta precede the onset of glucose intolerance and potentially contribute to the pathophysiology of GDM.