Cardiovascular diabetology · 2025
Metabolic pathways mediating insulin resistance and gestational diabetes mellitus discovered by high-dimensional systematic Mendelian randomization.
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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
Аннотация
BACKGROUND: 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.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.