Glycation is the nonenzymatic reaction of glucose, a-oxoaldehydes, and other sac-charide derivatives with proteins, nucleotides, and lipids, with formation of early gly-cation adducts (fructosamines) and advanced glycation end products (AGE). Formation of some AGE, i.e., pentosidine and ^E-[carboxymethyl]-lysine, combines both glycation and oxidative steps in a process termed "glycooxidation." In the last several years, the role for glycation/glycoxidation in diabetic complications including diabetic neuropathy has been extensively reviewed (63-65). A number of new studies in animal models of diabetes and human subjects support the role of this mechanism.
Using the state-of-the art technique, i.e., liquid chromatography with tandem mass spectrometry (MS) detection, Karachalias et al. (66) produced evidence of accumulation of fructosyl-lysine and AGE in peripheral nerve of STZ-diabetic rats. In particular, sciatic nerve concentrations of NMcarboxymethyl] -lysine and ^®-[carboxyethyl]-lysine were markedly increased in diabetic rats in comparison with controls. Hydroimidazolone AGEs derived from glyoxal, nethylglyoxal, and deoxyglucosone were major AGEs quantitatively. The receptor for AGE (RAGE) was localized both in endothelial and Schwann cells of the peripheral nerve (67). Recently generated RAGE-/- mice appeared partially protected from diabetes-associated pain perception loss, an indicator of long-standing diabetic neuropathy (68). Furthermore, in the same study, loss of pain perception was reversed in the diabetic wild-type mice treated with soluble RAGE. The new inhibitor of AGE and advanced lipoxidation end product (ALE) formation, pyridoxamine, previously reported to be effective against diabetic nephropathy and retinopathy was found to reverse established sciatic endoneurial NBF, MNCV, and SNCV deficits in STZ-diabetic rats with 8-week duration of diabetes (69). Of interest, this correction was achieved in the absence of any significant effect of the agent on the levels of AGE/ALEs, N-(carboxymethyl)lysine, and N-(carboxyethyl)lysine in total sciatic nerve protein, which suggests that short-term diabetes and pyridoxamine treatment target AGE/ALE in vasa nervorum rather than neural components of the peripheral nerve. Another new antiglycation agent OPB-9195 reduced sciatic nerve immunoreactive AGE expression, and prevented the slowing of tibial motor nerve conduction, downregulation of Na+, K+-ATPase activity, and accumulation of 8-hydroxy-2'-deoxyguanosine (a marker of DNA oxidative damage) in STZ-diabetic rats with 24-week duration of diabetes (70).
High-dose therapy of thiamine and benfotiamine, suppressed AGE accumulation in the peripheral nerve (66) and reversed diabetic neuropathy (71), potentially by reducing the levels of triose phosphates through activation of transketolase. Several in vitro studies describe adverse effects of AGE precursors and AGE per se in Schwann cells (72,73). In particular, methylglyoxal was found to induce rat Schwann cell apoptosis through oxidative stress-mediated activation of p38 MAPK (72). AGE derived from glyceraldehyde and glycolaldehyde, but not from glucose induced rat Schwann cell apoptosis, decreased cell viability and replication, decreased mitochondrial membrane potential, activated NF-kB, and enhanced production of inflammatory cytokines, i.e., tumor necrosis factor (TNF-a) and interleukin-P (73).
Several new studies support the presence of AGE accumulation in patients with diabetes mellitus. The AGE pyrraline immunoreactivity was more intense in the optic nerve head of diabetic subjects in comparison with nondiabetic controls (74). Pronounced AGE immunoreactivity was detected in axons and myelin sheaths in 90% of patients with type 2 diabetes, but not in control subjects, and the intensity of axonal AGE posi-tivity significantly correlated with the severity of morphological alterations characteristic for PDN (75). In the same study, AGE positivity was clearly present in endoneurium, perineurium, and microvessels of patients with diabetes. Bierhaus et al. (68) have demonstrated that ligands of RAGE, the receptor itself, activated NF-kB, p65, and inter-leukin-6 colocalized in the microvasculature of sural nerve biopsies obtained from human subjects with diabetic neuropathy. Furthermore, ^E-[carboxymethyl]-lysine, RAGE, and NF-kB were found in the sural nerve perineurium, epineurial vessels, and endoneurial vessels of subjects with impaired glucose tolerance-related polyneuropathy (76). Several clinical studies support the role of glycation in the pathogenesis of PDN and other diabetes complications (77-79). In particular, it has been reported that increased accumulation of skin AGE precedes and correlates with clinical manifestations of diabetic neuropathy (77). In another study, AGE accumulation in skin, serum, and saliva increased with progression of neuropathy, nephropathy, and retinopathy (78).
Furthermore, serum ^E-[carboxymethyl]-lysine concentrations were found significantly higher in children and adolescents with type 1 diabetes and diabetes complications (background retinopathy, microalbuminuria, and neuropathy) in comparison with the uncomplicated group (79).
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All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.