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

妊娠中后期的糖尿病妊娠会增加后代患2型糖尿病的风险。目前尚不清楚胎儿暴露在糖尿病环境中是如何使胎儿在成年后患糖尿病的。我的主管开发了一种新的代谢编程小鼠模型，在该模型中，糖尿病母亲的后代患上了2型糖尿病。成年后，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是异常的。该项目的总体假设是，高水平的葡萄糖从母亲的血液循环输送到胎儿体内，会导致胎儿组织发炎，从而调节出生后生命中的葡萄糖稳态，从而导致2型糖尿病。首先，我将测量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)的炎症标记物(氧化应激标记物、促炎细胞因子和激活的NF-κB)。然后，我将测试阻断炎症反应是否能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和使用在胰岛β细胞、肝脏、骨骼肌或脂肪中表达炎症信号通路抑制物的转基因小鼠来阻止炎症反应。

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.