Bidirectional Causal Associations Between Endogenous/Exogenous Antioxidant Levels and Risks of Type 1 and Type 2 Diabetes Mellitus and Three Complications

ABSTRACT Owing to the significant pathogenic role played by oxidative stress in diabetes mellitus, the associations between antioxidants and the incidence of diabetes mellitus have garnered much interest, while the findings are conflicting. The present study aimed to investigate the bidirectional causal connections underlying the relationship between circulating levels of eight endogenous and five exogenous antioxidants and the risks of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), as well as three complications: diabetic ketoacidosis, diabetic nephropathy, and diabetic retinopathy, by means of Mendelian randomization analyses. The analyses indicate that albumin and bilirubin may causally contribute to protection against the development of T1DM and T2DM, respectively. The exogenous β‐carotene is likely to act as a protective factor against the development of T2DM. Bilirubin may have a causally protective role in preventing the development of diabetic ketoacidosis. For the reverse analysis of diseases predicting antioxidant levels, T1DM, T2DM, and their complications were likely to be associated with varied levels of several antioxidants, but the effects are weak overall. Our analyses may provide useful clues that inform the use of antioxidants for preventing or predicting both diabetes mellitus and its complications.