The AGE/RAGE/NF-(kappa)B pathway may contribute to the pathogenesis of polyneuropathy in impaired glucose tolerance (IGT).

Binding of ligands to the receptor for advanced glycation end products (RAGE) results in activation of the transcription factor nuclear factor kappa B (NF-(kappa)B) and subsequent expression of NF-(kappa)B-regulated cytokines. This has been shown to be a relevant pathomechanism in diabetic polyneuropathies (PNP). To determine whether this pathway may contribute to the pathogenesis of PNP due to impaired glucose tolerance (IGT) we performed a pilot study to demonstrate the presence of the RAGE ligand N (epsilon)-(Carboxymethyl)lysine (CML), the receptor itself and N-(kappa)B in sural nerve biopsies of 4 patients with IGT-related PNP. Biopsies of either 4 patients with diabetic PNP and with Charcot-Marie-Tooth disease (CMT) I and II served as positive and negative controls, respectively. In IGT-related PNP and diabetic PNP, CML, RAGE, and NF-(kappa)B was found in the perineurium, epineurial vessels and in part in endoneurial vessels. CMT patients showed, if any, only weak staining for one or the other antigen. These data suggest that activation of the RAGE pathway may be one of the first steps in the pathogenesis of PNP even before chronic hyperglycemia occurs.