Abstract
Diabetes mellitus in early pregnancy can cause neural tube defects (NTDs) in embryos by perturbing protein activity, causing cellular stress, and increasing programmed cell death (apoptosis) in the tissues required for neurulation. Hyperglycemia augments a branch pathway in glycolysis, the hexosamine biosynthetic pathway (HBP), to increase uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc). GlcNAc can be added to proteins by O-GlcNAc transferase (OGT) to regulate protein activity. In the embryos of diabetic mice, OGT is highly activated in association with increases in global protein O-GlcNAcylation. In neural stem cells in vitro, high glucose elevates O-GlcNAcylation and reactive oxygen species, but the elevations can be suppressed by an OGT inhibitor. Inhibition of OGT in diabetic pregnant mice in vivo decreases NTD rate in the embryos. This effect is associated with reduction in global O-GlcNAcylation, alleviation of intracellular stress, and decreases in apoptosis in the embryos. These suggest that OGT plays an important role in diabetic embryopathy via increasing protein O-GlcNAcylation, and that inhibiting OGT could be a candidate approach to prevent birth defects in diabetic pregnancies.
Highlights
Congenital birth defects caused by maternal diabetes mellitus (DM) in early pregnancy are complications known as diabetic embryopathy[1, 2]
To determine whether the hexosamine biosynthetic pathway (HBP) pathway is involved in diabetic embryopathy, we quantified protein O-GlcNAcylation in the neural tube of embryos at E10.5, the late stage of neurulation (E8.5 to E11.5)[25]
To determine whether the elevation of O-GlcNAcylation is a result of O-GlcNAc transferase (OGT) activation, we examined the levels of activated form of OGT, i.e., phosphorylated at tyrosine residues[26]
Summary
Congenital birth defects caused by maternal diabetes mellitus (DM) in early pregnancy are complications known as diabetic embryopathy[1, 2]. Perturbation of mitochondrial activity leads to over-generation of reactive oxygen species (ROS) and oxidative stress in cells[6, 7]. Together, these cellular stress conditions induce excessive programmed cell death (apoptosis) in the neural epithelium, resulting in failure of neurulation[2]. GlcNAc can be added to proteins on serine or threonine residues via O-glycosidic linkage This reaction, known as O-GlcNAcylation, is catalyzed by O-GlcNAc transferase (OGT; Fig. 1)[10]. Glucose influx into cells accelerates intracellular glucose metabolism, an, potentially enhances the HBP pathway and augments protein O-GlcNAcylation[18, 19]. Diabetic animal models which mimic human diabetic pregnancy, may provide information for developing interventions to prevent birth defects in diabetic pregnancies
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