Glycochelates and the etiology of diabetic peripheral neuropathy.
People with diabetes are prone to develop peripheral vascular and nerve abnormalities which, in extreme cases, can lead to limb amputations. Although numerous theories have been advanced for these complications, no firm explanation is yet available. Recently, evidence has appeared suggesting that these vascular and nerve abnormalities may involve transition metals; administration of chelators such as desferrioxamine has been shown to prevent or actually reverse slowed peripheral nerve conduction and neuronal blood flow, as well as impaired endothelium-dependent arterial relaxation. Here, we argue that (i) the heavily glycated proteins known to accumulate in people with diabetes gain an increased affinity for transition metals such as iron and copper, (ii) as a result, proteins such as elastin and collagen within the arterial wall-which are known to be particularly heavily glycosylated in diabetes-may accumulate bound metal, especially copper, (iii) the bound metal causes the catalytic destruction of endothelium derived relaxing factor (nitric oxide or a derivative thereof), thereby engendering a state of chronic vasoconstriction. The resulting impairment of blood flow to peripheral nerves restricts the delivery of oxygen and nutrients and, in extremis, nerve death eventuates. If this hypothesis is proved correct, there are important implications for the development of novel pharmaceuticals for the treatment of diabetic peripheral neuropathy.
Qian
M
M
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Eaton
J W
JW
D000818:Animals; D002614:Chelating Agents; D003300:Copper / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000209:etiology* / Q000503:physiopathology; D006023:Glycoproteins / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D007501:Iron / Q000378:metabolism; D008954:Models, Biological; D010525:Peripheral Nerves / Q000503:physiopathology
D002614:Chelating Agents; D006023:Glycoproteins; D003300:Copper; D007501:Iron