Pregnancy Health and Beyond Laboratory, Flinders Health and Medical Research Institute, Flinders University, Adelaide, SA 5042, Australia.
Nutrients. 2022 Sep 22;14(19):3930. doi: 10.3390/nu14193930.
Folate is a dietary micronutrient essential to one-carbon metabolism. The World Health Organisation recommends folic acid (FA) supplementation pre-conception and in early pregnancy to reduce the risk of fetal neural tube defects (NTDs). Subsequently, many countries (~92) have mandatory FA fortification policies, as well as recommendations for periconceptional FA supplementation. Mandatory fortification initiatives have been largely successful in reducing the incidence of NTDs. However, humans have limited capacity to incorporate FA into the one-carbon metabolic pathway, resulting in the increasingly ubiquitous presence of circulating unmetabolised folic acid (uFA). Excess FA intake has emerged as a risk factor in gestational diabetes mellitus (GDM). Several other one-carbon metabolism components (vitamin B12, homocysteine and choline-derived betaine) are also closely entwined with GDM risk, suggesting a role for one-carbon metabolism in GDM pathogenesis. There is growing evidence from in vitro and animal studies suggesting a role for excess FA in dysregulation of one-carbon metabolism. Specifically, high levels of FA reduce methylenetetrahydrofolate reductase (MTHFR) activity, dysregulate the balance of thymidylate synthase (TS) and methionine synthase (MTR) activity, and elevate homocysteine. High homocysteine is associated with increased oxidative stress and trophoblast apoptosis and reduced human chorionic gonadotrophin (hCG) secretion and pancreatic β-cell function. While the relationship between high FA, perturbed one-carbon metabolism and GDM pathogenesis is not yet fully understood, here we summarise the current state of knowledge. Given rising rates of GDM, now estimated to be 14% globally, and widespread FA food fortification, further research is urgently needed to elucidate the mechanisms which underpin GDM pathogenesis.
叶酸是一种必需的膳食微量营养素，对一碳代谢至关重要。世界卫生组织建议在受孕前和孕早期补充叶酸（FA），以降低胎儿神经管缺陷（NTD）的风险。随后，许多国家（约 92 个）实施了强制性 FA 强化政策，以及推荐在受孕前补充 FA。强制性强化计划在很大程度上成功降低了 NTD 的发病率。然而，人类将 FA 纳入一碳代谢途径的能力有限，导致循环中未代谢的叶酸（uFA）的存在越来越普遍。FA 摄入过量已成为妊娠糖尿病（GDM）的一个风险因素。其他几种一碳代谢成分（维生素 B12、同型半胱氨酸和胆碱衍生的甜菜碱）也与 GDM 风险密切相关，表明一碳代谢在 GDM 发病机制中起作用。越来越多的体外和动物研究证据表明，FA 过量在一碳代谢失调中起作用。具体来说，高水平的 FA 会降低亚甲基四氢叶酸还原酶（MTHFR）的活性，使胸苷酸合成酶（TS）和蛋氨酸合成酶（MTR）的活性失衡，并使同型半胱氨酸升高。高同型半胱氨酸与氧化应激和滋养层细胞凋亡增加以及人绒毛膜促性腺激素（hCG）分泌和胰岛β细胞功能降低有关。虽然 FA 水平升高、一碳代谢失调与 GDM 发病机制之间的关系尚未完全阐明，但我们在此总结了目前的知识状况。鉴于 GDM 的发病率不断上升，目前估计全球发病率为 14%，以及 FA 食品强化的广泛应用，迫切需要进一步研究阐明支持 GDM 发病机制的机制。
