Metabolic vs. Vascular Abnormalities In Diabetic Neuropathy

The DCCT clearly implicates hyperglycemia as an important contributory factor in the pathogenesis of diabetic polyneuropathy, a multifaceted set of clinical syndromes reflective of widespread damage to peripheral nerve fibers. The biochemical cascade stemming from hyperglycemia and responsible for this disorder remains controversial. Recently published clinical trials in diabetic neuropathy with aldose reductase inhibitors implicate the aldose reductase pathway as an important component in this process. Activation of the aldose reductase pathway by hyperglycemia produces secondary derangements in NAD(P) + :NAD(P)H ratios, depletion of alternative intracellular osmolytes such as taurine and myo ‐inositol, and accelerated protein glycation. These biochemical alterations in turn can lead to the formation of reactive oxygen species (ROS), as can glucose‐related aldose‐reductase‐independent pathways such as auto‐oxidation and protein glycation. Aldose reductase‐dependent and aldose‐reductase‐independent ROS generation may directly damage end‐organ tissues or their vascular support, producing ischemia. Mitochondria are damaged by ROS, mitochondrial ROS generation is increased by imbalances in substrate and oxygen availability, and mitochondrial defense against ROS‐induced damage requires adequate energy supply. Hence metabolic oxidative stress from glucose and ischemic injury both target the mitochondria. Mitochondrial damage is an important initiator of programmed cell death, or apoptosis, through the release of mitochondrial cytochromes, and activation of caspase enzymes. This cascade of events, stemming from hyperglycemia, operating through aldose‐reductase‐dependent and aldose‐reductase‐independent generation of ROS, involving mitochondrial damage and impaired vascular support and tissue ischemia, and resulting in apoptosis, appears to play a potentially important role in the pathogenesis of chronic diabetic complications such as peripheral neuropathy.