The pathogenesis of diabetic neuropathy is uncertain. Hyperglycemia results in nerve ischemia in human diabetic neuropathy. It was critical to determine whether microvascular pathology plays a central pathogenetic role or whether the changes represent late stage or secondary changes. To approach this important issue we studied chronic streptozotocin (STZ) experimental diabetic neuropathy (EDN) seeking evidence of endoneurial hypoxia, and ischemia, at a stage before florid fiber degeneration resulted. It was necessary to demonstrate that endoneurial hypoxia preceeded fiber degeneration. We have made excellent progress in the past 8 years. The presence of endoneurial hypoxia is now well-established and mechanisms by which hyperglycemia results in hypoxia may include alterations in prostacyclin: thromboxane A2 and advanced glycosylation end-products. We propose to continue our ongoing studies on the pathogenesis of diabetic neuropathy, using STZ EDN. The major hypothesis is that EDN is a metabolic disorder, with the brunt borne by nerve microvessels. We plan to extend our microvascular physiologic studies from peripheral nerve axon to sensory and sympathetic neurons. We will further evaluate the role of chronic hyperglycemia on nerve trunk and ganglionic (sensory and sympathetic) blood flow and oxygen tension. We will evaluate the efficacy of aminoguanidine in reversing the abnormalities of nerve blood flow, oxygen tension and nerve conduction in chronic EDN, a study of great clinical significance. We will evaluate the role of oxygen free radical (OFR) activity in EDN, and the efficacy of measures that reduce OFR activity in improving nerve electrophysiology and the blood-nerve barrier. We plan to study the effect of exogenous insulin on oxygen release and endoneurial O2 tension in peripheral nerve and ganglia of EDN. We should also be able to mathematically model the effect of insulin on oxygen release. Several of these approaches are potentially applicable to the management of human diabetic neuropathy.
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