Department of Obstetrics, Gynecology and Reproductive Sciences,University of Maryland School of Medicine, Baltimore, Maryland, USA.
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Sci Rep. 2017 Sep 11;7(1):11107. doi: 10.1038/s41598-017-11655-6.
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.
妊娠早期的糖尿病可通过扰乱蛋白活性、导致细胞应激以及增加神经管形成所需组织中的程序性细胞死亡（细胞凋亡），从而引起胚胎神经管缺陷（NTDs）。高血糖会增强糖酵解的分支途径——己糖胺生物合成途径（HBP），从而增加尿苷二磷酸-N-乙酰葡萄糖胺（UDP-GlcNAc）。GlcNAc 可通过 O-连接糖基化转移酶（OGT）添加到蛋白质中，以调节蛋白活性。在糖尿病小鼠的胚胎中，OGT 与整体蛋白 O-连接糖基化的增加高度激活。在体外神经干细胞中，高葡萄糖会升高 O-连接糖基化和活性氧，但 OGT 抑制剂可抑制这些升高。体内抑制糖尿病妊娠小鼠的 OGT 会降低胚胎的 NTD 发生率。这种作用与整体 O-连接糖基化减少、细胞内应激缓解以及胚胎中细胞凋亡减少有关。这些表明 OGT 通过增加蛋白 O-连接糖基化在糖尿病胚胎病中发挥重要作用，并且抑制 OGT 可能是预防糖尿病妊娠中出生缺陷的候选方法。
