Localization in human diabetic peripheral nerve of N(epsilon)-carboxymethyllysine-protein adducts, an advanced glycation endproduct.

Abstract

The present study was designed to elucidate in situ distribution of advanced glycation endproducts (AGE) in human peripheral nerve and whether the reaction products were excessive in the diabetic condition. For the detection of AGE, immunoperoxidase staining was undertaken on peripheral nerve samples obtained from 5 non-insulin-dependent diabetic patients and 5 non-diabetic control subjects. The anti-AGE antibody used in this study contained an epitope against N(epsilon)-carboxymethyllysine. Light microscopically, AGE localized in the perineurium, endothelial cells and pericytes of endoneurial microvessels as well as myelinated and unmyelinated fibers. At the submicroscopic level, AGE deposition appeared focally as irregular aggregates in the cytoplasm of endothelial cells, pericytes, axoplasm and Schwann cells of both myelinated and unmyelinated fibers. Interstitial collagens, basement membranes of the perineurium also reacted with this antibody. The AGE depositions were detected in both control and diabetic nerves, but were more intense in the latter. The excessive AGE deposition correlated with a reduction in myelinated fiber density. However, the localization of AGE was not directly associated with degeneration of nerve fibers and the link between AGE deposition and nerve fiber degeneration is yet to be determined. The present study thus demonstrated the excessive deposition of intra- and extracellular AGE in human diabetic peripheral nerve and strengthened the contention that the enhanced glycation may play a role in the development of diabetic neuropathy.