Diabetic Peripheral Neuropathy: Possible Involvement of Iron Bound to Glycated Basement Membrane Proteins † 470

Abstract

Listen

Translate article

The etiology of peripheral nerve and vascular dysfunction in insulin-dependent diabetes mellitus is unknown, but experimental evidence indicates that defects in nitric oxide-mediated, endothelium-dependent vascular relaxation lead to diminished neuronal blood flow. We hypothesize that these peripheral nerve and vascular abnormalities arise from an accumulation of sub-endothelial iron - bound to glycated proteins of the internal elastic lamina - which effects the catalytic decomposition of nitric oxide. In support of this hypothesis: (1) The administration of iron chelators such as desferrioxamine and trientine fully corrects defective endothelium-dependent relaxation and nerve conduction velocity in diabetic rats (J. Clin. Invest. 96:1159, 1995). (2) Glycated bovine elastin and soluble collagen fragments (gelatin) bind iron (added as ferrous ammonium sulfate). Maximal bound iron ranges from 10-15 μmol/g glycated protein vs.<0.3 μmol/g non-glycated protein. (3) In preliminary studies, tissue sections from the area of the sciatic nerve in rats following 2 months of streptozotocin-induced diabetes were stained for iron (with a sensitive silver-based reaction). In many cases, extensive iron deposition was observed in the internal elastic laminae of large and small arteries of diabetic - but not control - animals. These findings support the hypothesis that, in diabetes, extensive glycation of basement membrane/internal elastic lamina proteins generates adducts capable of binding adventitious iron. The resultant subendothelial `glycochelates' catalytically destroy endothelium-derived nitric oxide, thereby contributing to an imbalance of vasodilator vs. vasoconstrictor factors and resulting in a state of relative chronic vasoconstriction. The diminished blood flow to peripheral nerves leads to neuronal hypoxia and eventual nerve death. If true, this provides a rationale for the administration of iron chelators for the prevention or even reversal of the peripheral vasculopathy and neuropathy of diabetes.