Project: Research project

Project Details


The pathogenesis of diabetic neuropathy is not known. 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 or secondary changes. To approach
this important issue we studied chronic streptozotocin (STZ) experimental
diabetic neuropathy (EDN) seeking 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 4 years. The
presence of endoneurial hypoxia is 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. 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 improving nerve electrophysiology and the
blood-nerve barrier. We plan to study the effect of exogenous insulin on
oxygen release and endoneurial O/2 tension in peripheral nerve and ganglia
of EDN. Several of these approaches are potentially applicable to the
management of human diabetic neuropathy.
Effective start/end date4/1/783/31/98


  • Medicine(all)
  • Neuroscience(all)