Developmental programming of type 2 diabetes during diabetic pregnancy: Involvement of hyperglycemia-induced inflammation during fetal development

妊娠中期至晚期的糖尿病妊娠会增加后代患2型糖尿病的风险。胎儿暴露于糖尿病环境中是如何“编程”胎儿在成年后患糖尿病的，目前还不清楚。我的导师开发了一种新的代谢规划小鼠模型，其中糖尿病母亲的后代患有2型糖尿病。作为成年人，它们的血糖水平高于非糖尿病小鼠的后代。胰岛素敏感性和葡萄糖刺激的胰岛素释放也异常。该项目的总体假设是，从母亲的循环输送到胎儿的高水平的葡萄糖引起胎儿组织中的炎症，从而调节出生后的葡萄糖稳态，导致2型糖尿病。首先，我将测量在胎儿和出生后调节葡萄糖稳态的组织（胰岛、肝脏、脂肪和肌肉）中的炎症标志物（氧化应激标志物、促炎细胞因子和活化的NF-κB）。然后，我将测试阻断炎症反应是否可以防止糖尿病小鼠后代患糖尿病。我将通过在怀孕期间使用抗氧化剂以及使用在胰腺β细胞、肝脏、骨骼肌或脂肪中表达炎症信号通路抑制剂的转基因小鼠来阻断炎症反应。

Diabetic pregnancy during mid- to late gestation increases the risk for type 2 diabetes in the off-spring. It is not known how fetal exposure to a diabetic environment “programs” the fetus for dia-betes in adult life. A new mouse model of metabolic programming was developed by my supervisor in which the offspring of diabetic mothers develop type 2 diabetes. As adults, their blood glucose levels are higher than offspring of nondiabetic mice. Insulin sensitivity and glucose-stimulated insulin release are also abnormal. The overall hypothesis of this project is that high levels of glucose transported from the mother’s circulation to the fetus causes inflammation in fetal tissues that regulate glucose homeostasis in postnatal life, leading to type 2 diabetes. First, I will measure markers of inflammation (markers of oxidative stress, proinflammatory cytokines, and activated NF-κB) in tissues that regulate glucose homeostasis (pancreatic islet, liver, fat, and muscle) during fetal and postnatal life. Then, I will test whether blocking the inflammatory response prevents the development of diabetes in the offspring of diabetic mice. I will block the inflammatory response by using antioxidants administered during pregnancy and by using transgenic mice that express an inhibitor of the inflammatory signaling pathway in the pancreatic beta cell, the liver, skeletal muscle, or fat.