Diabetic polyneuropathy (DPN) is the most common complication of diabetes and may frequently be the presenting symptom in type 2 diabetes mellitus (T2DM). Metabolic syndrome and T2DM are associated with multiple metabolic toxicities. These substrate toxicities support the formation of reactive oxygen species (ROS), which are so damaging to cells, tissues and organs and play an important role in the development of multiple diabetic complications. The importance of redox stress (ROS) and their effect on the neuronal unit are discussed. There are at least 5 major pathways involved in the development of DPN: metabolic, vascular, immunologic-autoimmune, neurohormonal growth factor deficiency, and extracellular matrix neuronal unit remodeling.
Each of these five pathways are reviewed and related to neural redox stress and the role of ROS. The identification of the toxic substrates (A-FLIGHT acronym), earlier diagnosis of T2DM at the stage of impaired glucose tolerance or impaired fasting glucose, and aggressive global risk reduction with the use of a simple RAAS acronym will assist the clinician in slowing the natural progressive history, and possibly preventing the complications associated with DPN.The pain, foot ulceration, limb loss, organ dysfunction, and the associated morbidity and financial burden all contribute to the need for a better understanding of DPN and the role of redox stress and global risk reduction.

Keywords: Diabetes Mellitus, Type 2 - metabolism, Diabetic Neuropathies - metabolism, Extracellular Matrix - metabolism, Metabolic Syndrome X - metabolism, Neurons - metabolism, Oxidation-Reduction, Reactive Oxygen Species - metabolism, Diabetes Mellitus, Type 2 - metabolism, Diabetic Neuropathies - metabolism, Extracellular Matrix - metabolism, Metabolic Syndrome X - metabolism, Neurons - metabolism, Oxidation-Reduction, Reactive Oxygen Species - metabolism