VASCULAR IRON DEPOSITION & DIABETIC COMPLICATIONS

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Humans and animals with diabetes develop peripheral nerve and vascular dysfunction. Interestingly, the early nerve blood flow and nerve conduction deficits in diabetic animals are fully corrected by administration of iron chelators such as desferrioxamine and trientine. As a potential explanation for this rather surprising effect of iron chelators, we hypothesize the following sequence of events (i) Elevated sugars lead to enhanced protein glycation, particularly in long-lived proteins such as elastin and collagen which are major constituents of the internal elastic laminae. (ii) Glycation of elastin and collagen produces structures which bind iron leading, in vivo, to the formation of a ferruginous barrier immediately beneath the endothelium. (iii) This iron-rich sub-endothelial protein matrix will - through iron-mediated processes - catalytically destroy endothelium-derived relaxing factor nitric oxide. (iv) The resultant defect in endothelium-dependent vascular r ela xation leads to vasoconstriction, chronic peripheral ischemia, and, finally, dysfunction and death of peripheral nerves. The objective of our experimental work with ESR are: (i) Attempt to determine the nature of the glycated protein:iron adducts(s), (ii) examine the extent to which these adducts interact with nitric oxide and, if possible, (iii) determine the life-span of the nitric oxide:iron:glycated protein complexes.