About half of all people with diabetes experience some degree of diabetic neuropathy, which can present either as polyneuropathy or mononeuropathy (109). Diabetic neuropathy can also affect the central and the autonomic nervous systems. Level of hyperglycemia seems to determine the onset and progression of diabetic neuropathy (110,111).
In vitro studies have shown that glycation of cytoskeletal proteins such as tubulin, actin, and neurofilament results in slow axonal transport, atrophy, and degeneration (110). Additionally, glycation of laminin, an important constituent of Schwann cell basal laminae, impairs its ability to promote nerve fiber regeneration (111). The process of glycation increases the permeability of proteins, albumin, nerve growth factor, and immunoglobulin G across the blood-nerve barrier (112) leading to protein accumulation in the central nervous system (113).
Diabetic rats show reduction in sensory motor conduction velocities and nerve action potentials and reduction in peripheral nerve blood flow and all these abnormalities can be prevented by pretreatment with anti-AGE agents such as aminoguanidine (114,115). Pentosidine content was increased in cytoskeletal proteins of the sciatic nerve of streptozotocin induced diabetic rats and decreased after islet transplantation (111).
Pentosidine content was found elevated in cytoskeletal and myelin protein extracts of sural nerve from human subjects (116). The sural and peroneal nerves of human diabetic subjects contain AGEs in the perineurium, endothelial cells, pericytes of endoneural microvessels, and in myelinated and unmyelinated fibers; a significant correlation has been observed between the intensity of CML accumulation and myelinated fiber loss (117). At the submicroscopic level, AGE deposition appeared focally, as irregular aggregates in the cytoplasm of endothelial cells, pericytes, axoplasm and Schwan cells of both myelinated and unmyelinated fibers. Interstitial collagen and basement membrane of the perineurium also exhibited similar deposits. The excessive accumulation of intra and extracellular AGEs in human diabetic peripheral nerve supports the view of a causative role for these substances in the development of diabetic neuropathy (117). Furthermore, AGE accumulation in the vasa nervorum could worsen wall thickening with occlusion and ischemia and secondarily segmental demyelination (118).
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