Abstract
BACKGROUND: The uric acid to high-density lipoprotein cholesterol ratio (UHR) has emerged as a novel metabolic marker and is proven to be associated with diabetes risk. However, there is still a lack of systematic research regarding its role in gender differences and underlying mechanisms. This study aims to assess the association of UHR with diabetes risk in the context of gender differences and to investigate its mediation effects through metabolic and inflammatory pathways. METHODS: This study utilized data from NHANES 2005-2010 and included 6,843 adult participants. Multivariate logistic regression was employed to assess the association between UHR and diabetes risk, and restricted cubic spline (RCS) along with correlation analysis was applied to explore its relationship with metabolic risk factors. Multiple mediation analysis was conducted to evaluate the mediating effects of homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides (TG), and C-reactive protein (CRP) on the association between UHR and diabetes risk. RESULTS: In the overall population, UHR was significantly positively associated with diabetes risk, but gender-stratified analysis revealed a stronger predictive effect in women. In the unadjusted model, every unit increase in UHR was linked to an 18.6% increase in diabetes risk in women (p < 0.001). In the quartile analysis, women in the highest quartile showed an 8.49-fold increased risk of diabetes (OR = 8.494, 95% CI: 5.542-13.019, p < 0.001), whereas no significant association was observed in men (p > 0.05). Mediation analysis revealed that HOMA-IR was the main mediator of the relationship between UHR and diabetes risk, with mediation effects of 64.55%, 118.38%, and 39.09% in the overall population, men, and women, respectively. Additionally, the mediation effect of TG was stronger in men (36.78%) and weaker in women (17.31%). The mediation effect of CRP was relatively minimal across all groups, accounting for 7.62% in men and 2.67% in women. CONCLUSION: This study demonstrates that the association between UHR and diabetes risk exhibits gender differences, with higher diabetes risk observed in women, while men show stronger mediation effects in insulin resistance, lipid metabolism, and inflammatory response.