Heavy Metal Mixture Exposure and Insulin Resistance in U.S. Adults: The Mediating Role of Systemic Inflammation

Exposure to heavy metals has been implicated in insulin resistance (IR), yet the mechanisms remain unclear. Systemic inflammation may link metal exposure to metabolic outcomes.

We analyzed 3042 U.S. adults from NHANES 2021-2023. Blood lead, cadmium, mercury, selenium, and manganese were examined in relation to IR (HOMA-IR), with high-sensitivity C-reactive protein (hs-CRP) as the inflammatory mediator. We used survey-weighted regression, Baron-Kenny mediation, and weighted quantile sum (WQS) regression for the mixture, stratified by sex; sensitivity analyses additionally adjusted for body mass index (BMI) and smoking.

In primary models, lead, cadmium, and mercury were inversely associated with HOMA-IR (lead β = -0.259), as was a WQS mixture dominated by these metals, and hs-CRP significantly mediated several associations. After additional adjustment for BMI and smoking, the inverse single-metal and mixture associations remained significant but were attenuated by roughly half, indicating substantial adiposity confounding. hs-CRP continued to mediate a smaller but significant share (roughly 10% to 30%, vs. 25% to 43% before adjustment). The positive manganese association did not survive BMI adjustment and is not robust. Mediation was larger in females and younger adults.

In a nationally representative sample, blood lead, cadmium, and mercury, individually and as a mixture, were inversely associated with insulin resistance, with hs-CRP mediating a smaller but significant share after adjustment for adiposity. Because the associations are substantially attenuated by BMI and the design is cross-sectional, reverse causation is plausible. These findings are hypothesis-generating and motivate prospective studies.