Glucose-induced endoplasmic reticulum stress is independent of oxidative stress: A mechanistic explanation for the failure of antioxidant therapy in diabetes

Oxidative stress contributes to the pathogenesis of diabetes and its complications. However, a large number of interventional studies have failed to show any health benefits of antioxidants. The overwhelming failure of antioxidant therapy to prevent disease can be explained by inadequacy of the doses of antioxidants used, short duration of therapy, or poor timing of initiation of the supplementation. A more likely reason for failure of antioxidants to reduce diabetes-related complications is the multiplicity of mechanisms of glucotoxicity that are independent of oxidative stress. Recently, endoplasmic reticulum (ER) stress has emerged as an important contributor to diabetes-related complications. Multiple lines of experimental evidence indicate that ER stress in endothelial cells can be uncoupled from oxidative stress induced by hyperglycemia, and antioxidants can ameliorate the latter without altering the ER stress. These observations provide a novel mechanistic explanation for the failure of antioxidant therapy in interventional clinical trials.