基于出生队列的孕期维生素D缺乏－代谢性炎症在母婴糖稳态受损中的作用及干预研究

Metaflammation has been widely regarded as the major mechanism underlying impaired glucose homeostasis. Our previous studies have found that vitamin D (VD) deficiency is associated with increased maternal and fetal inflammation and risk of gestational diabetes mellitus (GDM). Thus, we hypothesize that prenatal VD deficiency increases the susceptibility of impaired maternal and infant glucose homeostasis by driving metaflammation. Based on the established birth cohort, specific lipid metabolites associated with glucose homeostasis related inflammatory cytokines (TNF-α, etc) will be screened by using metabolomics technique among small sample and the metabolic pathway will be analyzed as well. Then, a large sample analysis will be conducted to confirm the relationships between prenatal 25(OH)D- specific lipid metabolites - inflammatory cytokines, and to explore whether prenatal VD deficiency promotes inflammatory response through specific lipid metabolism pathway. The glucose metabolic function of mother-infant pairs will be evaluated during pregnancy, delivery and the fourth year postpartum. Using orthogonal design (VD－inflammation ), we will assess whether prenatal VD deficiency increases the susceptibility of impaired maternal and infant glucose homeostasis. We will establish a new birth cohort. Pregnant women with VD deficiency will receive vitamin D3 supplementation from 8-16 gestational weeks to 32 gestational weeks. Oral glucose tolerance test will be conducted and peripheral blood sample will be collected. Inflammatory cytokines and specific lipid metabolites in blood sample before and after intervention will be detected. After delivery, cord blood and placenta will be collected to detect inflammatory cytokines, C peptide and HbA1c. We will evaluate whether prenatal VD supplementation inhibits metaflammation and reduces susceptibility of impaired maternal and fetal glucose homeostasis. From the perspective of disease susceptibility, this study will clarify the value of VD as a controllable regulatory factor of metaflammation in the protection of maternal and infant glucose homeostasis.

代谢性炎症是糖稳态受损的核心机制。前期研究发现VD缺乏与母胎炎症及GDM风险关联，推论VD缺乏通过驱动代谢性炎症增加母婴糖稳态受损易感性。基于已建出生队列，应用代谢组学技术小样本筛选与糖稳态相关炎症因子（TNF-α等）高度关联的孕外周特异脂代谢物，分析代谢通路。再大样本验证25(OH)D－特异脂代谢物－炎症因子间关系，探讨孕期VD缺乏是否通过特异脂代谢通路促进母胎炎症。进行孕期、出生时、产后第４年母子糖代谢评价，正交设计（VD－炎症）探讨VD缺乏是否增加母子糖稳态受损易感性。新建孕期干预队列，对VD缺乏孕妇补充VD3，孕24周后行OGTT并保存外周血。检测干预前后炎症因子和特异脂代谢物。分娩后收集脐血和胎盘，检测炎症因子、C肽和HbA1c。探讨孕期补充VD是否抑制代谢性炎症、降低母胎糖稳态受损易感性。本研究将从疾病易感性视角，阐明VD作为代谢性炎症的可控性调节因素在保护母婴糖稳态中的价值。

代谢性炎症是糖稳态受损的核心机制。前期研究发现维生素D（vitamin D, VD）缺乏与母胎炎症及GDM风险关联，推论VD缺乏通过驱动代谢性炎症增加母婴糖稳态受损易感性。基于合肥母婴健康队列，探讨孕期VD缺乏是否通过特异脂代谢促进母胎炎症增加母子糖稳态受损易感性。建立孕期维生素D干预队列，探讨孕期补充VD是否抑制代谢性炎症、降低母胎糖稳态受损易感性。初步阐明：（1）孕中期VD水平与脂代谢指标间存在非线性关系，仅在VD缺乏状态下，25(OH)D与脂代谢指标存在显著负相关；（2）妊娠期间高水平的维生素D可能改善脂质水平，并抑制高脂代谢引起的hs-CRP升高；（3）高水平25(OH)D可改善孕期空气污染引进的胎儿全身炎症和糖脂代谢；（4）孕期VD缺乏与空腹血糖水平增加显著关联，并增加GDM发生风险。而较高的孕期VD补充频率与GDM风险降低显著相关；（5）孕期VD与糖代谢的关联受PTH 水平的调节，VD 缺乏且伴有PTH 水平升高的孕妇存在更为明显的糖代谢异常；（6）孕期较高的25(OH)D浓度与较好的心血管健康（CVH）显著相关，而不良睡眠模式可改变这种关联；（7）较高的膳食炎症潜能（EDIP）评分可能通过促进炎症增加心血管风险（CVR）评分，充足的维生素D可通过抗炎降低CVR评分；（8）GDM孕妇补充VD可显著改善代谢组紊乱，花生四烯酸，咖啡酸和脱氧肌酐水平显著降低；（9）GDM孕妇孕期补充VD可降低空腹血糖水平、葡萄糖-甘油三脂指数，还可改善孕妇的内皮功能、降低10年心血管风险。基本完成项目预定的3个目标；探讨孕期VD缺乏是否通过特异脂代谢通路促进母胎代谢性炎症；阐明VD缺乏在代谢性炎症与母婴糖稳态受损关联中的作用；验证孕期补充VD是否抑制代谢性炎症并降低母胎糖稳态受损易感性。本项目通过前瞻性出生队列研究和随机对照临床试验研究，初步阐明“孕期VD缺乏通过特异脂代谢通路促进代谢性炎症增加母胎糖代谢稳态受损易感性”这一理论假设，为孕妇补充VD改善母子代谢紊乱提供了科研依据。