Begzati Arjana, Godinez-Macias Karla P, Long Tao, Watrous Jeramie D, Moranchel Rafael, Kantz Edward D, Tuomilehto Jaakko, Havulinna Aki S, Niiranen Teemu J, Jousilahti Pekka, Salomaa Veikko, Yu Bing, Norby Faye, Rebholz Casey M, Selvin Elizabeth, Winzeler Elizabeth A, Cheng Susan, Alotaibi Mona, Goyal Ravi, Ideker Trey, Jain Mohit, Majithia Amit R
Department of Medicine, University of California San Diego, La Jolla, CA.
Department of Pediatrics, University of California San Diego, La Jolla, CA.
Diabetes Care. 2025 Mar 1;48(3):473-480. doi: 10.2337/dc24-2266.
Plasma metabolite profiling has uncovered several nonglycemic markers of incident type 2 diabetes (T2D). We investigated whether such biomarkers provide information about specific aspects of T2D etiology, such as impaired fasting glucose and impaired glucose tolerance, and whether their association with T2D risk varies by race.
Untargeted plasma metabolite profiling was performed of participants in the FINRISK 2002 cohort (n = 7,564). Cox regression modeling was conducted to identify metabolites associated with incident T2D during 14 years of follow-up. Metabolites were clustered into pathways using Gaussian graphical modeling. Clusters enriched for T2D biomarkers were further examined for covariation with fasting plasma glucose (FPG), 2-h postchallenge plasma glucose (2hPG), HbA1c, or fasting insulin. Validation analyses and tests of interaction with race were performed in the Atherosclerosis Risk in Communities (ARIC) study.
Two clusters of metabolites, representing diacylglycerols (DAGs) and phosphatidylcholines (PCs), contained the largest number of metabolite associations with incident T2D. DAGs associated with increased T2D incidence (hazard ratio [HR] 1.22; 95% CI 1.14-1.30) independent of FPG, HbA1c, and fasting insulin, but not 2hPG. PCs were inversely associated with T2D risk (HR 0.78; 95% CI 0.71-0.85) independent of FPG, 2hPG, HbA1c, and fasting insulin. No significant interaction between DAGs or PCs and race was observed.
Fasting DAGs may capture information regarding T2D risk similar to that represented by 2hPG; PCs may capture aspects of T2D etiology that differ from those represented by conventional biomarkers. The direction of effect and strength of DAG and PC associations with incident T2D are similar across European and African Americans.
血浆代谢物谱分析已发现了几种2型糖尿病（T2D）发病的非血糖标志物。我们调查了这些生物标志物是否能提供有关T2D病因的特定方面的信息，如空腹血糖受损和糖耐量受损，以及它们与T2D风险的关联是否因种族而异。
对芬兰2002年队列研究（n = 7564）的参与者进行非靶向血浆代谢物谱分析。进行Cox回归建模以识别在14年随访期间与T2D发病相关的代谢物。使用高斯图形模型将代谢物聚类为通路。对富含T2D生物标志物的聚类进一步检查其与空腹血糖（FPG）、餐后2小时血糖（2hPG）、糖化血红蛋白（HbA1c）或空腹胰岛素的协变量。在社区动脉粥样硬化风险（ARIC）研究中进行验证分析和与种族的交互作用测试。
代表二酰甘油（DAGs）和磷脂酰胆碱（PCs）的两类代谢物与T2D发病的代谢物关联数量最多。DAGs与T2D发病率增加相关（风险比[HR] 1.22；95%置信区间1.14 - 1.30），独立于FPG、HbA1c和空腹胰岛素，但与2hPG无关。PCs与T2D风险呈负相关（HR 0.78；95%置信区间0.71 - 0.85），独立于FPG、2hPG、HbA1c和空腹胰岛素。未观察到DAGs或PCs与种族之间的显著交互作用。
空腹DAGs可能捕获与2hPG类似的有关T2D风险的信息；PCs可能捕获与传统生物标志物所代表的不同的T2D病因方面的信息。DAG和PC与T2D发病的关联效应方向和强度在欧洲裔和非裔美国人中相似。
