DIABETIC NEUROPATHY

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date4/1/923/31/97

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Neuroscience(all)

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