ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Cardiovascular Endocrinology
Plasma Ceramide Cer24:0 and Insulin Resistance: Associations with TyG and TG/HDL-C in a Multicenter Study of Coronary Artery Disease Cohorts
Shuanli Xin 1
Rui Wang 2
Xuejiao Chen 3
Chao Chang 1
Xiufeng Zhao 1
Yong Zeng 4
Liang Zhang 4
Mengdan Miao 1
Guidong Wang 1
Xiaopeng Li 1
Junwei Wang 1
Xin Zhang 1
Zhijiang Xie 1
1. Handan First Hospital Department of Cardiology, Handan, China
2. The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
3. Affiliated Hospital of Hebei Engineering University, Handan, China
4. Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing, China
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Abstract
Background: Insulin resistance (IR) is a key metabolic determinant of cardiovascular risk. Ceramides, a class of bioactive lipids, have been linked to IR; however, their clinical associations in patients with established coronary artery disease (CAD) are incompletely characterized. Methods: In a prospective, multicenter observational cohort of adults with established CAD (n=987), we quantified plasma ceramide species (Cer16:0, Cer18:0, Cer24:0, Cer24:1) and surrogate IR indices (triglyceride–glucose index (TyG), metabolic score for insulin resistance (METS-IR), and triglyceride–to–high-density lipoprotein cholesterol ratio (TG/HDL-C)). Mixed graphical models (MGM) were used to estimate conditional associations within a multivariable network. Double machine learning (DML) with causal-forest estimators provided covariate-adjusted association estimates and probed robustness values (RV) to unmeasured confounding. Exposures were standardized per standard deviation. We also developed a ceramide-augmented model to classify clinical IR, prespecified as TyG ≥ 9, and quantified discrimination by the area under the receiver operating characteristic curve (ROC–AUC). Results: Ceramides correlated with IR indices. In MGM analyses, Cer24:0 showed a direct conditional association with TyG (partial r=0.23; 95% CI, 0.17–0.29), independent of other variables in the network. In DML analyses, per 1-unit increase in ln (Cer24:0) was associated with higher TyG (estimate, 0.459; 95% CI, 0.252–0.665; P=0.001); These estimates demonstrated moderate RV to unmeasured confounding, with an RV (theta) of 0.223. A ceramide-augmented model classified clinical IR with an ROC–AUC of 0.770 (95% CI, 0.741–0.799). Conclusions: Across complementary analytic frameworks, Cer24:0 consistently exhibited positive associations with lipid-centric IR metrics among adults with established CAD. Although observational, these findings suggest that circulating ceramide profiling—particularly Cer24:0—may refine metabolic risk stratification beyond conventional indices in cardiology practice.
Summary
Keywords
Causal forest DML, Ceramides, Coronary Artery Disease, Insulin Resistance, Mixed graphical models
Received
29 December 2025
Accepted
10 February 2026
Copyright
© 2026 Xin, Wang, Chen, Chang, Zhao, Zeng, Zhang, Miao, Wang, Li, Wang, Zhang and Xie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zhijiang Xie
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