Zi-Qi Fang, Bing Wang, Ning‐hua Cui, Yang Zhe-zhe, Xuebin Wang
Exposure to metals has been associated with elevated oxidative stress, which may contribute to diabetic macrovascular complications. However, current methods for evaluating oxidative stress, which mainly rely on quantifying individual byproducts of oxidative damage, may not fully characterize the effects of metal exposure on global redox imbalance, especially in the setting of type 2 diabetes mellitus (T2DM). Here, by assessing global redox status using the novel marker oxidation-reduction potential (ORP) and performing elemental profiling of 35 plasma metals/metalloids in a large cohort of 3142 patients with T2DM, we successfully identified a mixture of 5 redox-related metals (including nickel, zirconium, titanium, strontium, and vanadium), which showed strong associations not only with ORP, but with conventional markers of protein, lipid, and DNA oxidation. Importantly, high exposure to the redox-related metal mixture cross-sectionally correlated with obstructive coronary artery disease (CAD) and prospectively predicted adverse events after percutaneous coronary intervention (PCI) in patients with T2DM. Further cytokine profiling found that changes in cytokines within the nuclear factor-kappa B (NF-κB) pathway might mediate the associations of the redox-related metal mixture with obstructive CAD and post-PCI outcomes. Notably, ex vivo experiments of peripheral blood mononuclear cells (PBMCs) showed that exposure to redox-related metals induced a specific pattern of bioenergetic dysfunction characterized by impaired respiration of mitochondrial complexes I and III, leading to mitochondrial oxidant overproduction and consequent NF-κB activation. Collectively, our findings indicate ORP as a promising marker of metal-induced oxidative stress and support the links of redox-related metals to cardiometabolic risk in patients with T2DM.