Determining the mediation role of CRP and IL-6 for associations between carotenoids, vitamin A, and vitamin E and insulin resistance in elderly

OBJECTIVES: This study aimed to investigate whether C-reactive protein (CRP) and interleukin-6 (IL-6) mediate the relationship between various antioxidants-specifically vitamin A, vitamin E isoforms, and carotenoids-and insulin resistance (IR). METHODS: We conducted a bias-corrected bootstrapping cross-sectional mediation analysis using biomarker data from the Midlife in the United States (MIDUS3) study (2017-2022). Antioxidants evaluated included Total lycopene, β-cryptoxanthin, retinol, and α- and γ-tocopherol. Insulin resistance was assessed using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). CRP and IL-6 were included as mediators. Analyses were adjusted for age, sex, waist-hip ratio (WHR), smoking status, physical activity, dyslipidemia (assessed via Total to HDL cholesterol ratio), and dietary quality, with all continuous covariates mean-centered. RESULTS: The analytic sample comprised 747 participants (56% female; mean age, 66 years; SD = 9.6). After adjustment, higher Total lycopene and β-cryptoxanthin levels were significantly associated with lower HOMA-IR, with no evidence of mediation by CRP or IL-6. In contrast, γ-tocopherol was associated with higher HOMA-IR, an effect partially mediated by elevated CRP (percent change per 10-unit increase: 7.79%; 95% CI: 2.12 to 18.53). Retinol showed significant indirect mediating associations through reduced CRP (-31.48%; 95% CI: -50.24 to -13.50) and IL-6 (-15.46%; 95% CI: -33.57 to-1.49), though these effects did not yield a significant total association. However, α-tocopherol didn't demonstrate a significant indirect or total association. CONCLUSION: Among older adults, γ-tocopherol was positively associated with insulin resistance, partially mediated by CRP, whereas β-cryptoxanthin and lycopene were inversely associated with HOMA-IR without a significant mediation for inflammatory markers. Although retinol reduced insulin resistance via reduced inflammatory markers, its overall association with insulin resistance was not significant.