Circulating claudin-5 as a marker of endothelial dysfunction in diabetic nephropathy: A comparative metabolic and insulin resistance analysis

Background: Endothelial dysfunction is a central mechanism in the development of diabetic nephropathy (DN). Claudin-5, a key endothelial tight-junction protein, plays an essential role in maintaining vascular barrier integrity. Alterations in circulating Claudin-5 may reflect endothelial injury associated with metabolic dysregulation in type 2 diabetes mellitus (T2DM).
Objective: To evaluate serum Claudin-5 levels in patients with T2DM with and without diabetic nephropathy and to assess its relationship with glycemic control, lipid profile, and insulin resistance indices, as well as its diagnostic performance for DN.
Methods: This comparative cross-sectional study included 90 participants divided into three groups: healthy controls (n=30), T2DM without nephropathy (n=30), and T2DM with diabetic nephropathy (n=30). Anthropometric measurements, glycemic indices, lipid profile, insulin resistance markers (HOMA-IR, HOMA-β, TyG index), and serum Claudin-5 levels were assessed. Group comparisons were performed using one-way ANOVA and Chi-square tests. Correlations were analyzed using Pearson and Spearman coefficients. Receiver operating characteristic (ROC) curve analysis evaluated the diagnostic performance of Claudin-5 alone and in combination with HbA1c and TyG index.
Results: Serum Claudin-5 levels differed significantly among the study groups (p = 0.003), showing a progressive decline from controls to T2DM patients, with the lowest levels observed in diabetic nephropathy. Claudin-5 correlated negatively with fasting glucose, HbA1c, total cholesterol, LDL-C, TyG index, and HOMA-IR, and positively with HDL-C and HOMA-β (all p < 0.05). ROC analysis demonstrated moderate discriminatory ability of Claudin-5 for DN (AUC = 0.682). HbA1c and TyG index showed superior performance, while a combined multivariable model incorporating Claudin-5, HbA1c, and TyG achieved the highest diagnostic accuracy (AUC = 0.886).
Conclusion: Reduced serum Claudin-5 is associated with metabolic dysregulation and insulin resistance in T2DM and reflects endothelial barrier dysfunction in diabetic nephropathy. Although not superior to established metabolic markers, Claudin-5 provides complementary value within a multimarker approach for DN risk stratification.