The Role of Oxidative Stress in the Pathophysiology of Gestational Diabetes Mellitus

Normal human pregnancy is considered a state of enhanced oxidative stress. In pregnancy, it plays important roles in embryo development, implantation, placental development and function, fetal development, and labor. However, pathologic pregnancies, including gestational diabetes mellitus (GDM), are associated with a heightened level of oxidative stress, owing to both overproduction of free radicals and/or a defect in the antioxidant defenses. This has important implications on the mother, placental function, and fetal well-being. Animal models of diabetes have confirmed the important role of oxidative stress in the etiology of congenital malformations; the relative immaturity of the antioxidant system facilitates the exposure of embryos and fetuses to the damaging effects of oxidative stress. Of note, there are only a few clinical studies evaluating the potential beneficial effects of antioxidants in GDM. Thus, whether or not increased antioxidant intake can reduce the complications of GDM in both mother and fetus needs to be explored. This review provides an overview and updated data on our current understanding of the complications associated with oxidative changes in GDM. Antioxid. Redox Signal. 15, 3061–3100. I. Introduction to Gestational Diabetes Mellitus A. Incidence B. Etiology and risk factors C. Short- and long-term risks of GDM 1. GDM increases the risk of metabolic complications in the mothers 2. GDM increases the risk of metabolic programming for the offspring 3. GDM modifies fetal growth pattern II. Brief Overview of Oxidative Stress A. Reactive oxygen species B. Antioxidants III. Brief Overview of Nitrative Stress IV. Oxidative Stress in the GDM Mother A. Oxidant species 1. Lipid peroxidation 2. Protein oxidation 3. Transitional metals B. Antioxidants 1. Nonenzymatic antioxidants 2. Enzymatic antioxidants 3. Transitional metals C. Concluding comments V. Oxidative Stress in the GDM Placenta and Fetus A. Oxidative stress in the placenta 1. ROS in the GDM placenta 2. Antioxidants in the GDM placenta 3. Reactive nitrogen species in the GDM placenta B. Oxidative stress and the fetus 1. Oxidative stress and fetal malformations 2. Nitrative stress and fetal malformations 3. Oxidative stress in the fetal organs 4. Oxidative stress in the umbilical cord of GDM women C. Concluding comments VI. Pathways Contributing to the Generation of Oxidative Stress in GDM A. Advanced glycation endproducts B. Hexosamine pathway C. Polyol pathway D. NADPH oxidase E. Protein kinase C F. Xanthine oxidase G. ROS production via mitochondria H. Concluding comments VII. The Biological Role of Oxidative Stress on Placental Function in GDM Pregnancies A. Inflammatory cytokines B. Metalloproteinases C. Apoptosis D. Vascular molecules E. Nuclear factor-kappa B F. Concluding comments VIII. The Role of Oxidative and Nitrative Stress in the Pathogenesis of GDM A. Decidualization and implantation B. Trophoblast invasion C. Organogenesis D. Endothelial and vascular dysfunction E. Placental nutrient transport mechanisms 1. Glucose transport a. Glucose metabolism in pregnancy b. Insulin signaling in GDM 2. Fatty acid transport 3. Amino acid transport 4. Placental ion transport mechanisms F. Cervical ripening and labor G. Intrauterine programming H. Concluding comments IX. Effects of Therapeutic Approaches on GDM A. Can antioxidant treatment reduce oxidative stress in GDM? B. Flavonoids as potential antioxidant supplements to reduce oxidative stress in GDM C. PPARs as targets to reduce oxidative and nitrative stress in GDM X. Future Directions XI. Conclusions