Advances in diabetes for the millennium: new treatments for diabetic neuropathies.

Diabetic neuropathies are not a single disorder but a heterogeneous group of conditions that involves different parts of the somatic and autonomic nervous systems. Neuropathies may be focal or diffuse, proximal or distal. The focal neuropathies are either entrapment syndromes that occur in 30% of patients with diabetes, and if recognized can be treated with diuretics, splinting local steroids, and unentrapment. The focal mononeuritides are vascular assaults and heal spontaneously and need supportive therapy. The proximal neuropathies are, for the most part, inflammatory demyelinating conditions that occur 11 times more frequently in the diabetic population and respond well to intravenous immunoglobulin (Ig)G or immunosuppressive treatments. The distal symmetric polyneuropathies are usually a mixed picture of sensorimotor dysfunction, and recent evidence based on intraepidermal nerve-fiber changes has identified a subset of painful neuropathies that are associated with impaired glucose tolerance and dysmetabolic syndrome, and precede the onset of diabetes. Pain in neuropathy is also multifactorial and can occur at different levels, starting at the peripheral sympathetic nervous system in the skin (C fibers) and migrating to involve A-beta and A-delta fibers to produce allodynia, continuing with reorganization at the cord-level, cold allodynia, and finally, within the central nervous system, spontaneously as opposed to provoked pain. This is best treated with agents that target the different levels of pain production. It now seems that the pathogenesis of diabetic neuropathy is also heterogeneous with causative factors, including microvascular insufficiency, oxidative stress, nitrosative stress, defective neurotrophism, and autoimmune-mediated nerve destruction. New therapies are aimed at the underlying pathogenesis as well as the symptom complex. If attention is directed toward a pathogenetic approach, much can be done to alleviate the symptoms, alleviate the mitigation of quality of life, and now it would seem to address the underlying biological disturbance.