Diabetes mellitus in early pregnancy causes birth defects by disturbing metabolic homeostasis and increasing programmed cell death in the embryo. Over-activation of phospholipase Cβ3 and γ1 suggests disturbed phospholipid metabolism, which is an important in regulation of cell signaling and activity. Metabolomic examinations reveal significant changes in the profile of phospholipid metabolism. Among the metabolites, levels of phosphatidylinositol bisphosphate (PIP2) are increased. PIP2 effector PTEN (phosphatase and tensin homolog deleted on chromosome 10) is activated. Activation of protein kinase Bα (PKBα, or AKT1) and mTOR (mechanistic target of rapamycin) is decreased. Inhibition of PLCs and PTEN suppresses over-generation of reactive oxygen species and inhibition of PLCs prevents fragmentation of mitochondria in neural stem cells cultured in high glucose. These observations suggest that maternal hyperglycemia disrupts phospholipid metabolism, leading to perturbation of mitochondrial dynamics and redox homeostasis and suppression of the PKB-mTOR cell survival signaling in the embryos.
Keywords: AKT; Diabetic embryopathy; Mitochondrion; PKB; PTEN; Phospholipid; Reactive oxygen species; mTOR.
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