Elevated Levels of Serum Alpha-2-Macroglobulin Associate with Diabetes Status and Incident Cardiovascular Disease in Type 1 Diabetes

Baohai Shao; Janet K Snell-Bergeon; Ian H de Boer; W Sean Davidson; Karin E Bornfeldt; Jay W Heinecke

doi:10.1016/j.jlr.2025.100741

Elevated Levels of Serum Alpha-2-Macroglobulin Associate with Diabetes Status and Incident Cardiovascular Disease in Type 1 Diabetes

J Lipid Res. 2025 Jan 4:100741. doi: 10.1016/j.jlr.2025.100741. Online ahead of print.

Authors

Baohai Shao¹, Janet K Snell-Bergeon², Ian H de Boer³, W Sean Davidson⁴, Karin E Bornfeldt³, Jay W Heinecke³

Affiliations

¹ Department of Medicine, University of Washington, Seattle, WA 98109. Electronic address: bhshao@uw.edu.
² Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045.
³ Department of Medicine, University of Washington, Seattle, WA 98109.
⁴ Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45237.

PMID: 39761918
DOI: 10.1016/j.jlr.2025.100741

Abstract

Background: Atherosclerotic cardiovascular disease (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.

Study design: We used isotope dilution-tandem mass spectrometry 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.

Findings: Out of the 28 serum proteins studied, 5 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% confidence interval of 1.8-6.1.

Conclusions: 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.

Keywords: Alpha-2-macroglobulin; Cox proportional regression; atherosclerosis; case-cohort design; incident cardiovascular disease; mass spectrometry; parallel reaction monitoring; proteomics.