Department of Obstetrics and Gynaecology, Peking University First Hospital, Beijing 100034, China.
Beijing Key Laboratory of Maternal Foetal Medicine of Gestational Diabetes Mellitus, Beijing 100034, China.
Chin Med J (Engl). 2024 Jul 5;137(13):1563-1575. doi: 10.1097/CM9.0000000000002840. Epub 2023 Oct 24.
BACKGROUND: Alterations in the placental expression of glucose transporters (GLUTs), the crucial maternal-fetal nutrient transporters, have been found in women with hyperglycemia in pregnancy (HIP). However, there is still uncertainty about the underlying effect of the high-glucose environment on placental GLUTs expression in HIP. METHODS: We quantitatively evaluated the activity of mammalian target of rapamycin (mTOR) and expression of GLUTs (GLUT1, GLUT3, and GLUT4) in the placenta of women with normal pregnancies (CTRL, n = 12) and pregnant women complicated with poorly controlled type 2 diabetes mellitus (T2DM, n = 12) by immunohistochemistry. In addition, BeWo cells were treated with different glucose concentrations to verify the regulation of hyperglycemia. Then, changes in the expression of GLUTs following the activation or suppression of the mTOR pathway were also assessed using MHY1485/rapamycin (RAPA) treatment or small interfering RNA (siRNA)-mediated silencing approaches. Moreover, we further explored the alteration and potential upstream regulatory role of methyltransferase-like 3 (METTL3) when exposed to hyperglycemia. RESULTS: mTOR, phosphorylated mTOR (p-mTOR), and GLUT1 protein levels were upregulated in the placenta of women with T2DM compared with those CTRL. In BeWo cells, mTOR activity increased with increasing glucose concentration, and the expression of GLUT1, GLUT3, and GLUT4 as well as GLUT1 cell membrane translocation were upregulated by hyperglycemia to varying degrees. Both the drug-mediated and genetic depletion of mTOR signaling in BeWo cells suppressed GLUTs expression, whereas MHY1485-induced mTOR activation upregulated GLUTs expression. Additionally, high glucose levels upregulated METTL3 expression and nuclear translocation, and decreasing METTL3 levels suppressed GLUTs expression and mTOR activity and vice versa . Furthermore, in METTL3 knockdown BeWo cells, the inhibitory effect on GLUTs expression was eliminated by activating the mTOR signaling pathway using MHY1485. CONCLUSION: High-glucose environment-induced upregulation of METTL3 in trophoblasts regulates the expression of GLUTs through mTOR signaling, contributing to disordered nutrient transport in women with HIP.
背景：在患有妊娠性高血糖症（HIP）的女性中，发现葡萄糖转运体（GLUTs）的胎盘表达发生改变，GLUTs 是重要的母胎营养转运体。然而，高糖环境对 HIP 中胎盘 GLUTs 表达的潜在影响仍存在不确定性。
方法：我们通过免疫组织化学定量评估了正常妊娠（CTRL，n=12）和合并未控制 2 型糖尿病（T2DM，n=12）孕妇胎盘的雷帕霉素靶蛋白（mTOR）活性和 GLUTs（GLUT1、GLUT3 和 GLUT4）的表达。此外，用不同浓度的葡萄糖处理 BeWo 细胞以验证高血糖的调节作用。然后，用 MHY1485/雷帕霉素（RAPA）处理或小干扰 RNA（siRNA）介导的沉默方法评估 mTOR 通路激活或抑制后 GLUTs 表达的变化。此外，我们还进一步探讨了暴露于高血糖时甲基转移酶样 3（METTL3）的改变及其潜在的上游调节作用。
结果：与 CTRL 相比，T2DM 孕妇胎盘的 mTOR、磷酸化 mTOR（p-mTOR）和 GLUT1 蛋白水平升高。在 BeWo 细胞中，mTOR 活性随葡萄糖浓度的增加而增加，GLUT1、GLUT3 和 GLUT4 的表达以及 GLUT1 细胞膜易位也不同程度地上调。BeWo 细胞中 mTOR 信号的药物介导和遗传耗竭均抑制 GLUTs 表达，而 MHY1485 诱导的 mTOR 激活则上调 GLUTs 表达。此外，高葡萄糖水平上调 METTL3 表达和核易位，降低 METTL3 水平抑制 GLUTs 表达和 mTOR 活性，反之亦然。此外，在 METTL3 敲低的 BeWo 细胞中，用 MHY1485 激活 mTOR 信号通路可消除对 GLUTs 表达的抑制作用。
结论：滋养细胞中高糖环境诱导的 METTL3 上调通过 mTOR 信号调节 GLUTs 的表达，导致 HIP 女性中营养物质转运紊乱。
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