Pathology and pathogenesis of diabetic neuropathy

Two coherent features underpin the pathology of human diabetic neuropathy: nerve fibers degenerate and blood vessels supplying them are grossly diseas ed. Unless one naively assumes that the blood vessels play no role in the m aintenance of normal nerve function, the failure to link microangiopathy wi th neuropathy may well be perceived as a major failing to adequately addres s the pathogenesis of human diabetic neuropathy. Yet, until the last 10 yea rs, the role of vascular factors in the pathogenesis of diabetic neuropathy was denied or seriously questioned. However, the recent explosion of data from animal models Supported by in vivo and pathological studies in diabeti c patients, provides incontrovertible evidence that microangiopathy plays a crucial role in the pathogenesis of nerve damage. Furthermore, the develop ment of a significant microangiopathy may form the critical point, which de termines whether or not nerve fibers repair themselves or proceed to total degeneration and hence clinically relevant neuropathy. While hyperglycemia and many of its Secondary transducers, including the polyol pathway, glycat ion, and oxidative stress, may contribute to peripheral nerve degeneration, and neurotrophins to regeneration, the keg control mechanism lies in the v asculature. therapeutic intervention with a range vasoactive drugs improves nerve function in animal models, Promising results in diabetic patients ha ve also been achieved using a range of therapies, including large-vessel re vascularization, ACE inhibitors, gamma-linoleic acid, and alpha-lipoic acid . We await the results of large clinical trials involving therapies acting, ia the vascular axis to truly test the clinical relevance of the vascular h ypothesis thus aid in the development of a meaningful treatment for human d iabetic neuropathy.