Mechanisms leading to neuronal degeneration in hyperglycemia involve reactive oxygen species (ROS) formation. The diabetic state produces impaired neurotropism, axonal transport and gene expression through at least four major pathways. 1) Excess glucose is diverted away from glycolysis by the polyol pathway that depletes NADPH and cellular antioxidant capacity. 2) Glucose also may become oxidized and form AGEs that alter extracellular matrix, activate receptors that produce ROS intermediates, and alter intracellular protein function. 3) PKC becomes activated either directly by glycolytic intermediates or indirectly as shown as a second messenger for stress hormones, leading to increased vascular disease, inflammation, and oxidative stress. 4) Partial glycolysis causes accumulation of glycolytic intermediates and leads to escape of fructose-6-phosphate along the hexosamine pathway that increases vascular disease and further ROS generation. These mechanisms are ultimately linked to superoxide production through increased glucose respiration that produces superoxide in the mitochondria and also activates the superoxide-producing NADH oxidase. GSSG, glutathione disulfide; TCA, tricarboxylic acid cycle.