Diabetic autonomic neuropathy is an important clinical problem resulting in a significant increase in the morbidity and mortality of diabetes. In order to investigate the pathogenesis of diabetic autonomic neuropathy and its amelioration, which represent the long term objectives of this investigation, we have developed a highly reproducible neuropathologic model of experimental diabetic autonomic neuropathy. The regular occurrence of degenerating, regenerating, and dystrophic unmyelinated axons has been demonstrated in the ileal mesentery and distal alimentary tract of rats with chronic streptozotocin-induced diabetes. In studies recently completed, detailed characterization of the ultrastructural appearance of axonal lesions, time course of development, anatomic distribution, and immunocytochemical evidence for the involvement of post-ganglionic sympathetic axons has been accomplished. We have succeeded in completely preventing the development of the neuropathy using pancreatic islet transplantation or daily insulin therapy instituted within a few weeks of induction of the diabetic state and we have achieved nearly complete resolution of established neuropathy following pancreatic islet transplantation. The proposed studies will continue the detailed characterization of the neuropathy using ultrastructural, morphometric, biochemical, immunocytochemical and physiologic methods. Several possible pathogenic mechanisms will be examined to clarify the role of alterations of axonal transport in the development of the axonopathy, to investigate the role of sorbitol and myoinositol metabolism in its pathogenesis, and to examine the effect of age on its development. The hypothesis that the distinctive axonal lesions of experimental diabetic autonomic neuropathy represent frustrated axonal regeneration will be tested definitively. We will determine the physiologic consequences of experimental diabetic neuropathy involving the innervation of the alimentary tract. We will determine if the pathogenetic mechanisms we develop are specific for diabetic autonomic neuropathy by examining acrylamide autonomic neuropathy, which we have found has many structural features in common with the unmyelinated axonopathy of experimental diabetes.
