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World J Diabetes. Sep 15, 2025; 16(9): 110590
Published online Sep 15, 2025. doi: 10.4239/wjd.v16.i9.110590
Indirect bilirubin is inversely associated with diabetic retinopathy risk and is a potential predictive biomarker
Xiao-Ying Lin, Yi-Xuan Zheng, Meng-Meng Liu, Qian Liang, Meng Li, Jing Sui, Wei Qiang, Hui Guo, Bing-Yin Shi, Ming-Qian He
Xiao-Ying Lin, Yi-Xuan Zheng, Qian Liang, Meng Li, Wei Qiang, Hui Guo, Bing-Yin Shi, Ming-Qian He, Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Meng-Meng Liu, Department of Endocrinology, Xi’an Gaoxin Hospital, Xi’an 710075, Shaanxi Province, China
Jing Sui, Department of Endocrinology and International Medical Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Ming-Qian He, Med-X Institute, Center for Immunological and Metabolic Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Co-corresponding authors: Bing-Yin Shi and Ming-Qian He.
Author contributions: Lin XY contributed to the conceptualization, methodology, software, validation, visualization, writing—original draft preparation, and writing—review and editing; Zheng YX and Liu MM contributed to the formal analysis and data curation; Liang Q contributed to the investigation; Li M, Sui J, and Qiang W contributed to resources and funding acquisition; Guo H helped supervise the study; Shi BY helped supervise the study and contributed to project administration; He MQ contributed to conceptualization, methodology, validation, resources, writing—original draft preparation, writing—review and editing, supervision, project administration, and funding acquisition. As co-corresponding authors, Shi BY and He MQ played important roles in the preparation and administration of this study. The collaboration between Shi BY and He MQ was essential for the publication of this manuscript and therefore qualifies them as co-corresponding authors of the paper.
Supported by Natural Science Foundation of Shaanxi Province, No. 2024JC-YBQN-0828 and No. 2024JC-YBMS-765; Clinical Research Award of the First Affiliated Hospital of Xi'an Jiaotong University, No. XJTU1AF-CRF-2022-036; and National Innovation Center for Advanced Medical Devices, No. NMED2023AGP-013.
Institutional review board statement: The study was reviewed and approved by the Ethic Committees of the First Affiliated Hospital of Xi’an Jiaotong University (Approval No. XJTU1AF2018 LSK- 055).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: There is no conflict of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at mingqian_he@xjtufh.edu.cn. Consent was not obtained but the presented data are anonymized and risk of identification is low.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ming-Qian He, MD, Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, Xi’an 710061, Shaanxi Province, China. mingqian_he@xjtufh.edu.cn
Received: June 12, 2025
Revised: July 10, 2025
Accepted: August 19, 2025
Published online: September 15, 2025
Processing time: 93 Days and 21.4 Hours
Abstract
BACKGROUND

Diabetic retinopathy (DR) is a major cause of visual impairment and blindness. However, the current DR biomarkers are insufficient for accurately predicting its onset.

AIM

To identify a novel marker for predicting the risk of developing DR in patients with type 2 diabetes mellitus (T2DM).

METHODS

We conducted a cross-sectional study involving 6993 hospitalized T2DM patients between 2013 and 2020. Patients were divided into two groups: The DR group and the non-DR group. Data were analyzed using univariate, correlation, multivariate, subgroup, and receiver operating characteristic curve analyses.

RESULTS

Total bilirubin, indirect bilirubin (IBIL), and direct bilirubin were negatively correlated with the risk of developing DR (P < 0.001). Moreover, these three factors were all positively correlated with clinical indicators related to DR, including the estimated glomerular filtration rate, the albumin/creatinine ratio, and the 1,25-dihydroxyvitamin D3 level (P < 0.001). After adjusting for multiple variables, greater IBIL levels remained independently associated with a lower risk of developing DR (odds ratio = 0.500; 95% confidence interval: 0.363-0.686; P < 0.001). The optimal IBIL cutoff point for predicting the risk of DR in male patients with elevated diastolic blood pressure was 0.655 μmol/dL (area under the curve = 0.662).

CONCLUSION

These findings suggest that IBIL could be a valuable biomarker for predicting DR risk, offering a noninvasive, cost-effective, and readily available clinical tool for the early identification of high-risk patients. Future multicenter and longitudinal studies are warranted to validate these findings and further explore the biological mechanisms underlying the protective role of IBIL in DR.

Keywords: Biomarker; Diabetic retinopathy; Indirect bilirubin; Oxidative stress; Type 2 diabetes mellitus

Core Tip: This cross-sectional study distinguished the role of indirect bilirubin (IBIL) in diabetic retinopathy (DR) risk in patients with type 2 diabetes mellitus. While total and direct bilirubin showed some protective effects, only higher IBIL levels remained independently associated with a lower risk of developing DR after comprehensive multivariable adjustment (odds ratio = 0.500; 95% confidence interval: 0.363-0.686; P < 0.001). IBIL is thus a potential predictive biomarker for DR.