High-normal Serum Bilirubin is a Useful Indicator to Assess the Risk of Diabetic Retinopathy in Type 2 Diabetes: A Real-world Study

Overview

Journal Heliyon

Specialty Social Sciences

Date 2024 Aug 19

PMID 39157310

Authors

Man-Rong Xu

Jun-Wei Wang

Yi-Lin Ma

Yu-Jie Wang

Meng-Han Li

Jun-Xi Lu

Lian-Xi Li

Affiliations

Soon will be listed here.

Abstract

Background: To investigate the association of serum bilirubin within normal range, especially unconjugated bilirubin (UCB), with diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM).

Methods: In this cross-sectional, real-world study, 7617 T2DM patients were stratified into quartiles based on serum UCB levels. DR was determined by digital fundus photography and further classified into non-proliferative diabetic retinopathy (NPDR) and PDR. The associations of serum bilirubin levels and UCB quartiles with DR were investigated by logistic regression analysis.

Results: After controlling for age, sex, and diabetes duration, the DR prevalence was significantly decreased across the serum UCB quartiles (40.4 %, 33.4 %, 29.7 %, 26.6 % for each quartile, respectively, p < 0.001 for trend). The subjects with DR had lower serum total bilirubin (TB) and UCB, rather than conjugated bilirubin (CB), compared with those without DR (p = 0.003 for TB, p < 0.001 for UCB, and p = 0.528 for CB, respectively), while all three types of serum bilirubin in the subjects with PDR were obviously lower than those with NPDR (p = 0.006 for TB, and p < 0.001 for UCB and CB, respectively). After adjustment for confounding factors, logistic regression demonstrated negative associations of serum TB and UCB levels, rather than CB, with the presence of DR (OR: 0.844, 95%CI: 0.774-0.920, p < 0.001 for TB; OR: 0.828, 95%CI: 0.763-0.899, p < 0.001 for UCB; and OR: 0.984, 95%CI: 0.900-1.074, p = 0.713 for CB, respectively). Additionally, a fully-adjusted analysis revealed a negative correlation between UCB quartiles and DR (p < 0.001).

Conclusion: High-normal serum TB and UCB were closely associated with the decreased odds of DR, while all types of serum bilirubin were negatively correlated with the severity of DR in T2DM patients. Serum bilirubin may be used as a potential indicator to assess the risk and severity of DR in T2DM.

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References

Li T, Wang A, Lu J, Chen M, Zhao C, Tang Z . Prevalence and clinical characteristics of non-alcoholic fatty liver disease in newly diagnosed patients with ketosis-onset diabetes. Diabetes Metab. 2018; 44(5):437-443. DOI: 10.1016/j.diabet.2018.03.002. View

Najam S, Sun J, Zhang J, Xu M, Lu J, Sun K . Serum total bilirubin levels and prevalence of diabetic retinopathy in a Chinese population. J Diabetes. 2013; 6(3):221-7. DOI: 10.1111/1753-0407.12085. View

Xu M, Jin C, Lu J, Li M, Li L . High-normal unconjugated bilirubin is associated with decreased risk of chronic kidney disease in type 2 diabetes: A real-world study. Diabetes Metab Res Rev. 2023; 39(6):e3672. DOI: 10.1002/dmrr.3672. View

Wan H, Zhu H, Wang Y, Zhang K, Chen Y, Fang S . Associations between different bilirubin subtypes and diabetic microvascular complications in middle-aged and elderly individuals. Ther Adv Endocrinol Metab. 2020; 11:2042018820937897. PMC: 7357000. DOI: 10.1177/2042018820937897. View

Li L, Li M, Lu J, Jia L, Zhang R, Zhao C . Retinal microvascular abnormalities are associated with early carotid atherosclerotic lesions in hospitalized Chinese patients with type 2 diabetes mellitus. J Diabetes Complications. 2014; 28(3):378-85. DOI: 10.1016/j.jdiacomp.2014.02.004. View

Jin C, Wang J, Ke J, Li J, Li M, Li L . Low-normal serum unconjugated bilirubin levels are associated with late but not early carotid atherosclerotic lesions in T2DM subjects. Front Endocrinol (Lausanne). 2022; 13:948338. PMC: 9667095. DOI: 10.3389/fendo.2022.948338. View

Eid S, Sas K, Abcouwer S, Feldman E, Gardner T, Pennathur S . New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism. Diabetologia. 2019; 62(9):1539-1549. PMC: 6679814. DOI: 10.1007/s00125-019-4959-1. View

Neuzil J, Stocker R . Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation. J Biol Chem. 1994; 269(24):16712-9. View

Zhu Y, Cai X, Liu Y, Hu M, Zhou L, Liu W . Serum Albumin, but not Bilirubin, is Associated with Diabetic Chronic Vascular Complications in a Chinese Type 2 Diabetic Population. Sci Rep. 2019; 9(1):12086. PMC: 6700065. DOI: 10.1038/s41598-019-48486-6. View

10.

Rohatgi A, Westerterp M, von Eckardstein A, Remaley A, Rye K . HDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research. Circulation. 2021; 143(23):2293-2309. PMC: 8189312. DOI: 10.1161/CIRCULATIONAHA.120.044221. View

11.

Kang Q, Yang C . Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biol. 2020; 37:101799. PMC: 7767789. DOI: 10.1016/j.redox.2020.101799. View

12.

Salomone F, Volti G, Rosso C, Grosso G, Bugianesi E . Unconjugated bilirubin, a potent endogenous antioxidant, is decreased in patients with non-alcoholic steatohepatitis and advanced fibrosis. J Gastroenterol Hepatol. 2013; 28(7):1202-8. DOI: 10.1111/jgh.12155. View

13.

Chen M, Zhao C, Li T, Zhu Y, Yu T, Bao Y . Serum uric acid levels are associated with obesity but not cardio-cerebrovascular events in Chinese inpatients with type 2 diabetes. Sci Rep. 2017; 7:40009. PMC: 5209679. DOI: 10.1038/srep40009. View

14.

Karuppannasamy D, Venkatesan R, Thankappan L, Andavar R, Devisundaram S . Inverse Association between Serum Bilirubin Levels and Retinopathy in Patients with Type 2 Diabetes Mellitus. J Clin Diagn Res. 2017; 11(2):NC09-NC12. PMC: 5376786. DOI: 10.7860/JCDR/2017/24259.9452. View

15.

Inoguchi T, Sasaki S, Kobayashi K, Takayanagi R, Yamada T . Relationship between Gilbert syndrome and prevalence of vascular complications in patients with diabetes. JAMA. 2007; 298(12):1398-400. DOI: 10.1001/jama.298.12.1398-b. View

16.

Kudo K, Inoue T, Sonoda N, Ogawa Y, Inoguchi T . Relationship between serum bilirubin levels, urinary biopyrrin levels, and retinopathy in patients with diabetes. PLoS One. 2021; 16(2):e0243407. PMC: 7877782. DOI: 10.1371/journal.pone.0243407. View

17.

Narayanan S, Shosha E, Palani C . Spermine oxidase: A promising therapeutic target for neurodegeneration in diabetic retinopathy. Pharmacol Res. 2019; 147:104299. PMC: 7011157. DOI: 10.1016/j.phrs.2019.104299. View

18.

Hansen T, Wong R, Stevenson D . Molecular Physiology and Pathophysiology of Bilirubin Handling by the Blood, Liver, Intestine, and Brain in the Newborn. Physiol Rev. 2020; 100(3):1291-1346. DOI: 10.1152/physrev.00004.2019. View

19.

Liu M, Wang J, He Y . The U-Shaped Association between Bilirubin and Diabetic Retinopathy Risk: A Five-Year Cohort Based on 5323 Male Diabetic Patients. J Diabetes Res. 2018; 2018:4603087. PMC: 6232811. DOI: 10.1155/2018/4603087. View

20.

Novak P, Jackson A, Zhao G, Yin K . Bilirubin in metabolic syndrome and associated inflammatory diseases: New perspectives. Life Sci. 2020; 257:118032. DOI: 10.1016/j.lfs.2020.118032. View