Shao Baohai, Snell-Bergeon Janet K, de Boer Ian H, Davidson W Sean, Bornfeldt Karin E, Heinecke Jay W
Department of Medicine, University of Washington, Seattle, WA.
Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO.
J Lipid Res. 2025 Feb;66(2):100741. doi: 10.1016/j.jlr.2025.100741. Epub 2025 Jan 4.
Atherosclerotic CVD is a major cause of death in individuals with type 1 diabetes mellitus (T1DM). However, conventional risk factors do not fully account for the increased risk. This study aimed to investigate whether serum proteins associate with diabetes status and the occurrence of CVD in T1DM. We used isotope dilution-MS/MS to quantify 28 serum proteins in 228 subjects participating in the prospective Coronary Artery Calcification in Type 1 Diabetes study. We used linear regression to analyze the association between serum protein levels and T1DM status using 47 healthy controls and 134 T1DM patients without CVD and Cox proportional hazards regression to assess their prediction for incident CVD by a case-cohort study using a subcohort of 145 T1DM subjects and a total of 47 CVD events. Of the 28 serum proteins studied, five of them-alpha-2-macroglobulin (A2M), apolipoprotein A-IV, apolipoprotein L1, insulin-like growth factor 2, and phospholipid transfer protein-were significantly associated with T1DM status, with A2M being 1.6-fold higher in T1DM. After adjusting for potential confounders, A2M independently predicted incident CVD, with a mean hazard ratio of 3.3 and 95% CI of 1.8-6.1. In our study, A2M showed the largest increase in serum levels when comparing patients with T1DM to control subjects. A2M also predicted incident CVD, suggesting that it could serve as both a marker and possibly a mediator of atherosclerosis in T1DM. These findings emphasize the importance of specific serum proteins in assessing and managing CVD risk in T1DM.
动脉粥样硬化性心血管疾病（CVD）是1型糖尿病（T1DM）患者的主要死因。然而，传统风险因素并不能完全解释其增加的风险。本研究旨在调查血清蛋白是否与T1DM患者的糖尿病状态及CVD的发生相关。我们使用同位素稀释-质谱/质谱法对参与1型糖尿病前瞻性冠状动脉钙化研究的228名受试者的28种血清蛋白进行定量。我们采用线性回归分析47名健康对照者和134名无CVD的T1DM患者血清蛋白水平与T1DM状态之间的关联，并通过病例队列研究，利用145名T1DM受试者的亚队列和总共47例CVD事件，采用Cox比例风险回归评估血清蛋白对CVD发病的预测作用。在所研究的28种血清蛋白中，其中5种——α-2-巨球蛋白（A2M）、载脂蛋白A-IV、载脂蛋白L1、胰岛素样生长因子2和磷脂转运蛋白——与T1DM状态显著相关，T1DM患者的A2M水平高1.6倍。在调整潜在混杂因素后，A2M可独立预测CVD发病，平均风险比为3.3，95%置信区间为1.8至6.1。在我们的研究中，与对照组相比，T1DM患者的血清中A2M水平升高最为显著。A2M还可预测CVD发病，表明它可能是T1DM动脉粥样硬化的标志物及潜在介质。这些发现强调了特定血清蛋白在评估和管理T1DM患者CVD风险中的重要性。
