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

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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.