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

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.