Association of Serum Bile Acid and Unsaturated Fatty Acid Profiles with the Risk of Diabetic Retinopathy in Type 2 Diabetic Patients

Susu Feng,1 Lin Guo,1 Sijing Wang,1 Lijuan Chen,1 Hang Chang,2 Bo Hang,2,3 Jianhua Mao,2 Antoine M Snijders,2 Yibing Lu,1 Dafa Ding1 1Department of Endocrinology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; 3Department of Biomaterials, Berkeley-Nanjing Research Center, Nanjing, People’s Republic of ChinaCorrespondence: Dafa Ding, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiang Jia Yuan, Nanjing, 210011, People’s Republic of China, Tel +86 15850514014, Email dingdafa@njmu.edu.cnAim: We aimed to identify the ability of serum bile acids (BAs) and unsaturated fatty acids (UFAs) profiles to predict the development of diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM) patients.Methods: We first used univariate and multivariate analysis to compare 15 serum BA and 11 UFA levels in healthy control (HC) group (n = 82), T2DM patients with DR (n = 58) and T2DM patients without DR (n = 60). Forty T2DM patients were considered for validation. Then, the receiver operating characteristic curve (ROC) and decision curve analysis were used to assess the diagnostic value and clinical benefit of serum biomarkers alone, clinical variables alone or in combination, and the area under the curve (AUC), integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were used to further assess whether the addition of biomarkers significantly improved the predictive ability of the model.Results: Orthogonal partial least squares-discriminant analysis (OPLS-DA) of serum BAs and UFAs separated the three cohorts including HC, T2DM patients with or without DR. The difference in serum BA and UFA profiles of T2DM patients with or without DR was mainly manifested in the three metabolites of taurolithocholic acid (TLCA), tauroursodeoxycholic acid (TUDCA) and arachidonic acid (AA). Together, they had an AUC of 0.785 (0.918 for validation cohort) for predicting DR in T2DM patients. After adjusting for numerous confounding factors, TLCA, TUDCA, and AA were independent predictors that differentiated T2DM with or without DR. The results of AUC, IDI, and NRI demonstrated that adding these three biomarkers to a model with clinical variables statistically increased their predictive value and were replicated in our independent validation cohort.Conclusion: These findings highlight the association of three metabolites, TLCA, TUDCA and AA, with DR and may indicate their potential value in the pathogenesis of DR.Keywords: type 2 diabetes mellitus, diabetic retinopathy, serum bile acid, unsaturated fatty acid