Effect of Gestational Diabetes on Placental Development

妊娠期糖尿病对胎盘发育的影响

• 批准号: 10289571
• 负责人: Laura Clamon SCHULZ
• 金额: $ 7.91万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10289571
• 关键词: Acute; Address; Affect; Animal Model; Beta Cell; Blood Vessels; Cell Proliferation; Communication; Data; Development; Diet; Disease; Fatty acid glycerol esters; Fetus; First Pregnancy Trimester; Functional disorder; Gene Expression; Genes; Gestational Diabetes; Glucose; Glucose Intolerance; Goals; Histologic; Histology; Hormones; Human; Hypertrophy; Infant; Infant Health; Insulin; Insulin Resistance; Insulin deficiency; Islets of Langerhans; Lead; Life; Maternal Health; Measures; Mus; Obesity; Partner in relationship; Patients; Placenta; Placental Lactogen; Placentation; Pregnancy; Pregnancy Complications; Pregnant Women; Production; Regulation; Research; Risk; Sampling; Second Pregnancy Trimester; Signal Transduction; Structure of beta Cell of islet; Testing; Thinness; Third Pregnancy Trimester; Time; Ultrasonography; Villous; Weight; Woman; angiogenesis; cell growth; density; diet-induced obesity; early detection biomarkers; early pregnancy; feeding; glucose tolerance; impaired glucose tolerance; insulin secretion; insulin sensitivity; islet; mouse model; obesity risk; offspring; potential biomarker; precision medicine; prepregnancy; sugar; transcriptomics

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.

概括 在正常怀孕期间，孕产妇胰岛素敏感性在第二和三个月下降，以允许 葡萄糖递送到胎儿，而母体β细胞肿块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 不宽容。在某些患者中，尤其是那些肥胖的患者，胰岛素耐药过多会驱动这种不匹配， 而在其他患者，尤其是瘦女性的患者中，胰岛素缺乏症是主要因素。有需要 为了解决这些患者中GDM的不同原因的研究。拟议的项目将利用 小鼠模型是由类似于瘦女性的GDM的急性高脂肪进食引起的；它们是葡萄糖不耐剂 仅在怀孕期间，胰岛素耐药性，但β细胞增殖失败和胰岛素分泌减少。 初步表明，饮食特别干扰了胎盘刺激的β细胞增殖。 GDM女性的大量胎盘组织学数据表明，胎盘绒毛的成熟和 血管生成在期限被破坏。此外，与胎盘中的血管生成相关的基因以及与 在小鼠模型中，对胰岛中胎盘信号的响应在短期内被破坏。在一起 调查结果表明，胎盘功能在GDM中被破坏，以对两者的影响有助于 母亲和婴儿健康。拟议项目的目的1是将配对的胎盘样品配置为 正常妊娠的妊娠过程，以及鼠标中GDM复杂的妊娠过程以识别中断 胎盘β细胞交叉通信。 AIM 2将检查怀孕初期的胎盘血管生成和 在小鼠模型和使用超声中，在具有GDM的女性中。这些研究将在一起 显示胎盘的改变是否在葡萄糖不耐症的发作之前是否有助于 GDM的病理生理。