妊娠期糖尿病对子代骨骼发育影响的证据整合及机制研究进展

Gestational diabetes mellitus and skeletal development in offspring：evidence synthesis and mechanistic perspectives

摘要

妊娠期糖尿病(gestational diabetes mellitus，GDM)是妊娠期常见代谢性并发症，可通过宫内代谢编程影响子代骨骼发育。现有证据显示，GDM暴露与子代早期线性生长改变、骨量积累或骨质量形成异常、远期骨折风险升高及部分骨骼相关先天性异常有关，但不同研究结果并不一致，尚不能简单推断GDM与上述骨骼结局之间存在直接因果关系。围绕“代谢负荷启动—胎盘界面重塑—胎儿骨微环境改变—骨发育程序偏移”这一链条，宫内高糖的强度、持续时间和发生窗口可能经线粒体功能障碍、氧化应激、低度炎症、胰岛素/胰岛素样生长因子(insulin like growth factor，IGF)轴异常、Wnt/β-catenin和骨形态发生蛋白(bone morphogenetic protein，BMP)信号失衡、胎盘钙磷转运受限及表观遗传重塑，影响间充质干细胞成骨/成脂分化、生长板软骨细胞成熟、成骨细胞矿化和骨重塑稳态。GDM相关骨骼效应更可能呈现“早期扰动—部分代偿—风险遗留”的动态特征。未来需整合母体血糖时程、胎盘多组学、脐带血骨代谢标志物、子代骨微结构和骨折结局，建立骨骼结局导向的风险分层与干预体系。

Abstract

Gestational diabetes mellitus(GDM)is a common metabolic complication of pregnancy and may influence offspring skeletal development through intrauterine metabolic programming. Available evidence links GDM exposure to altered early linear growth，abnormal bone mass accrual or bone quality，increased fracture risk in later life，and a higher probability of selected skeletal congenital anomalies. However，results from different studies are inconsistent，and it is not yet possible to simply infer a direct causal relationship between GDM and the above skeletal outcomes. A mechanistic sequence can be proposed in which maternal metabolic load initiates placental-interface remodeling，modifies the fetal bone microenvironment，and shifts skeletal developmental programs. The intensity，duration，and timing of intrauterine hyperglycemia may affect mesenchymal stem cell osteogenic-adipogenic balance，growth - plate chondrocyte maturation，osteoblast mineralization，and bone remodeling through mitochondrial dysfunction，oxidative stress，low-grade inflammation，insulin/ insulin like growth factor(IGF)-axis disturbance，Wnt/β-catenin and bone morphogenetic protein(BMP)signaling imbalance，impaired placental calcium - phosphate transport，and epigenetic remodeling. Thus，the skeletal impact of GDM is more likely to follow a dynamic pattern characterized by early disruption，partial compensation，and residual risk rather than by a fixed reduction in bone density. Future studies should integrate maternal glycemic trajectories，placental multi-omics，cord-blood bone metabolic markers，offspring bone microarchitecture，and fracture outcomes to develop bone-oriented risk stratification and intervention strategies.

关键词

妊娠期糖尿病 / 子代 / 骨骼发育 / 宫内环境

Key words

gestational diabetes mellitus / offspring / skeletal development / intrauterine environment

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基金资助

国家科技重大专项(2024ZD0532103)

国家自然科学基金(82371697)

常州医学中心临床科研项目(CMCC202313)