E-selectin, but not CRP, partially mediates the association between metabolic indices and insulin resistance in older adults: a mediation analysis.

Background: Evidence on the pathophysiology of insulin resistance (IR), particularly the mediating role of inflammatory markers, remains limited. Objectives: Prior studies suggest associations of C-reactive protein (CRP) and E-selectin with IR, generally examined independently of other risk factors. This study evaluates their potential mediation roles. Methods: Using biomarker data from the Midlife in the United States 3 (MIDUS3) 2017-2022 cohort, we conducted cross-sectional bias-corrected bootstrapping mediation analyses to assess whether CRP and E-selectin mediate associations between established risk factors-body mass index (BMI), waist-hip ratio (WHR), total cholesterol/HDL ratio, age, glycated hemoglobin A (HbA1c), smoking status, dietary habits, physical activity, medication use, and sex-and IR measured by log-transformed homeostatic model assessment of IR (HOMA-IR). Results: The study included 708 participants (57% female; mean age 66.2 ± 9.65 years). CRP did not mediate associations between covariates and HOMA-IR. In contrast, E-selectin showed indirect-only mediation for sex and HOMA-IR (% change in HOMA-IR [%CHIR] in females = 2.4; 95% CI: [0.46, 5.80]). Partial mediation by E-selectin was observed for HbA1c (%CHIR = 9.26; 95% CI: [3.40, 18.66]), BMI (%CHIR = 2.72; 95% CI: [0.97, 5.54]), and total/HDL cholesterol ratio (%CHIR = 1.92; 95% CI: [0.34, 4.49]). Indirect-only mediation was also found for age (%CHIR = -1.11; 95% CI: [-2.58, -0.27]), non-smoking (%CHIR = -1.55; 95% CI: [-4.09, -0.13]), and higher healthy eating index score (%CHIR = -7.87; 95% CI: [-17.48, -2.43]). Conclusion: E-selectin, but not CRP, mediates relationships between metabolic risk factors and IR, highlighting endothelial dysfunction as a key pathway.