Chen Wei, Luo Mingjuan, Guo Jingyi, Wang Suna, Yan Dandan, Feng Xiaohui, Huang Yunting, Zeng Tao, Shen Li, Zhang Rong, Yan Jing, Hu Cheng, Zhang Weituo, Yu Xiangtian
Clinical Research Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Endocrinology and Metabolism, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
Cardiovasc Diabetol. 2025 May 9;24(1):195. doi: 10.1186/s12933-025-02746-0.
Gestational diabetes mellitus (GDM), characterized by insulin resistance (IR) and β-cell dysfunction, is one of the most common complications of pregnancy with unmet needs of prevention methods.
To investigate the causal role of insulin resistance and metabolic pathways in the pathogenesis of GDM with our proposed high-dimensional systematic Mendelian randomization (hdsMR) framework.
Cases with GDM and controls with normal glucose tolerance were recruited at the University of Hong Kong-Shenzhen Hospital from 2015 to 2018. A total of 566 participants (aged > 18 years), including 274 with GDM, were enrolled after excluding subjects with major chronic diseases or long-term use of medications affecting glycolipid metabolism. Clinical characteristics and serum samples were collected during the GDM screening stage, and the genome and metabolome were tested. A novel hdsMR framework was proposed to estimate the causal role of IR index (Homeostasis Model Assessment of Insulin Resistance, HOMA-IR) and metabolic pathways in the pathogenesis of GDM.
Our hdsMR method confirmed that HOMA-IR was causal to GDM (odds ratio, 1.17; 95% confidence interval, 1.04-1.32) and revealed that two metabolic pathways (glyoxylate and dicarboxylate metabolism pathway and lysine degradation pathway) mediated 14.6% and 8.4%, respectively, between HOMA-IR and GDM. In an independent validation cohort comprising 255 pre-diabetic individuals, we showed that both pathways could be intervened through diet (P < 0.05). Furthermore, glyoxylate and dicarboxylate metabolism pathway was significantly associated with adverse pregnancy outcomes in GDM.
These results indicated that targeting specific metabolic pathways through dietary intervention is worth exploring as a possible GDM prevention approach, and hdsMR is more efficient in finding causal mediating metabolic pathways than traditional MR methods.
妊娠糖尿病（GDM）以胰岛素抵抗（IR）和β细胞功能障碍为特征，是妊娠最常见的并发症之一，其预防方法仍未满足需求。
采用我们提出的高维系统孟德尔随机化（hdsMR）框架，研究胰岛素抵抗和代谢途径在GDM发病机制中的因果作用。
2015年至2018年在香港大学深圳医院招募GDM患者和糖耐量正常的对照。排除患有重大慢性病或长期使用影响糖脂代谢药物的受试者后，共纳入566名参与者（年龄>18岁），其中274名患有GDM。在GDM筛查阶段收集临床特征和血清样本，并进行基因组和代谢组检测。提出了一种新的hdsMR框架，以估计IR指数（胰岛素抵抗稳态模型评估，HOMA-IR）和代谢途径在GDM发病机制中的因果作用。
我们的hdsMR方法证实HOMA-IR对GDM具有因果关系（优势比，1.17；95%置信区间，1.04-1.32），并揭示两条代谢途径（乙醛酸和二羧酸代谢途径以及赖氨酸降解途径）分别在HOMA-IR和GDM之间介导了14.6%和8.4%的关系。在一个由255名糖尿病前期个体组成的独立验证队列中，我们表明这两条途径均可通过饮食进行干预（P<0.05）。此外，乙醛酸和二羧酸代谢途径与GDM的不良妊娠结局显著相关。
这些结果表明，通过饮食干预靶向特定代谢途径作为一种可能的GDM预防方法值得探索，并且hdsMR在发现因果介导代谢途径方面比传统MR方法更有效。
