Relationship between rates of oxidant generation, antioxidant activity, oxidative stress, and oxidative damage in diabetes. [O2]* represents various forms of reactive oxygen species [ROS]. The overall rate of formation of oxidative products leading to oxidative tissue damage is dependent on ambient levels of both [O2]* and substrate. Increased generation of [O2]* depends on several sources including glucose autoxidation, increased mitochondrial superoxide production, and as a result of the receptor for advanced glycosylation end products activation. [O2]* deactivation is reduced because antioxidant defenses are compromised in diabetes. Note that oxidative stress also promotes other hyperglycemia-induced mechanisms of tissue damage. Oxidative stress activates protein kinase C (PKC) and accelerates the formation of advanced glycosylation endproducts (AGEs).