Association of Blood Cadmium and Lead with the Risk of Diabetic Foot Ulcers: The Suppression Effect of Hemoglobin (NHANES 1999-2004)

Abstract

Background

Diabetic foot ulcer (DFU) is one of the most severe complications of diabetes, with hemoglobin (HGB) and inflammatory markers playing pivotal roles in its pathogenesis. However,the modifying effects of interactions between blood cadmium (Cd) and lead (Pb) exposure and these biological indicators on the risk of DFU remain unclear. This study evaluates how Cd and Pb exposure contributes to DFU risk, with a specific focus on the potential mediating role of HGB.

Methods

Data were obtained from the National Health and Nutrition Examination Survey (NHANES) 1999–2004. A total of 1633 participants (including 132 with DFU and 1501 Non-DFU) were included in the final analysis. Weighted logistic regression and restricted cubic splines (RCS) assessed associations between blood cadmium (Cd), lead (Pb), HGB, and DFU. Mediation analysis explored HGB's regulatory role in the Cd–DFU pathway, supplemented by subgroup analyses.

Results

After adjusting for all covariates, Blood Cd level was significantly associated with DFU risk (OR = 1.84; 95% CI:1.17–2.90, P = 0.01).RCS revealed a potential non-linear dose-response relationship with a risk threshold at 1.268 nmol/L, beyond which risk escalated sharply. In contrast,HGB served as an independent protective factor for DFU(OR = 0.73; 95% CI:0.60-0.87, P < 0.001).Notably, a positive correlation was observed between Blood Cd and HGB levels(β = 0.33, P < 0.001). Mediation analysis demonstrated that HGB exerted a significant suppression effect on the Cd–DFU association, accounting for −35.79% of the total effect (P = 0.04). Subgroup analyses identified higher DFU susceptibility among smokers (OR = 2.63;95%CI: 1.78-3.78), males, and individuals with elevated HbA1c levels.

Conclusion

Blood Cd is a significant risk factor for the development of DFU, while HGB provides a compensatory suppression effect that partially buffers Cd-induced toxicity. These findings suggest that elevated HGB levels in people with diabetes may mask the true risks associated with blood Cd, potentially leading to a significant underestimation of DFU risk in clinical practice.