Several studies have shown that the levels of

Several studies have shown that the levels of reactive dicarbonyls are higher in patients with diabetes as a result of hyperglycemia.49, 50, 51 Consequently, reactive dicarbonyl-derived AGEs are elevated in plasma and accumulate in tissues prone to secondary complications, including the lens, retina, kidney, and endothelial vessels of both diabetic humans and rodents.52, 53, 54, 55, 56 Indeed, the concentration of AGEs in the sciatic nerve of diabetic rats is higher than in nondiabetic rodents.53, 57 Extensive accumulation of AGEs also occurs in the skin and peripheral nerves of diabetic patients particularly in the axoplasm of myelinated and unmyelinated neurons, Schwann cells, endoneurial and epineurial microvessels, perineurial basal lamina, and perineurium, suggesting AGEs have a role in the development and/or progression of neuropathies.58, 59, 60, 61, 62, 63 A recent study investigated skin autofluorescence as a measure of AGE deposition in nondiabetic and diabetic subjects with or without neuropathy and found a correlation between slowing of sensory nerve conduction velocity (SNCV) and increased autofluorescence. Similarly, the levels of serum carboxymethyl lysine (CML) or skin autofluorescence were significantly higher in type 1 diabetic patients with microvascular complications, like neuropathy, compared with those without complications.65, 66
RAGE AGEs produce neuronal damage and dysfunction by a variety of mechanisms. AGEs interact with cell surface receptors, particularly the receptor for advanced glycation endproducts or RAGE, to induce a cascade of intracellular signaling (Fig 1). RAGE is a multiligand member of the immunoglobulin superfamily of cell surface receptors that signals through the phosphatidylinositol-3 kinase (PI-3K), Ki-Ras, and mitogen-activated protein kinase (MAPK) pathways. RAGE is present in the dorsal root ganglion (DRG), peripheral nerves, Schwann cells, and epidermal fibers in rodents. Transient activation of PI-3K/AKT and MAPK pathways leads to nuclear translocation of NF-κB.59, 68 NF-κB is responsible for the expression of different Adaptaquin receptor of genes including pro-inflammatory cytokines. IL-6 and TNF-α are particularly potent cytokines that have been shown to be elevated in the sciatic nerve of diabetic mice and to contribute to the pro-inflammatory state of diabetic neuropathy. Continual activation of NF-κB leads to altered gene expression and upregulation of RAGE creating a positive feedback loop that enhances sensory neuron damage. RAGE also stimulates NAD(P)H oxidase, a potent producer of reactive oxygen species (ROS) (Fig 1). Like glycating agents, excessive ROS alters proteins, lipids, and DNA causing damage to peripheral neurons. Rodent models of diabetes mellitus have demonstrated a role for RAGE in peripheral sensory nerve damage and neuropathy symptoms. Diabetic RAGE–/– mice were protected from both electrophysiological and morphological deficits of the peripheral nervous system demonstrated by diabetic wild-type mice. Similarly, the diabetes-induced loss of thermal pain perception and increased nociceptive thresholds were reduced in diabetic RAGE–/– mice. Patients with diabetes also exhibit increased immunoreactivity for RAGE and AGEs in sural nerve biopsies, which suggests that AGE–RAGE interaction may also have a role clinically in neuronal dysfunction that leads to neuropathy.
Protein Modification by Ages The pathophysiological consequences of AGE accumulation have been investigated in normal aging and in disease states such as Alzheimer’s disease, renal failure, inflammation, and some diabetic complications.71, 72, 73, 74 Several mechanisms are thought to mediate AGE damage in disease. In tissues, AGE modification of structural and cellular proteins, lipids, and nucleic acids results in dysfunction of vital cellular processes with limited proteasomal degradation, increased aggregation, and enhanced half-life of glycated proteins.35, 68 Although several proteins, which differ in structure and function, are known targets of the glycation process, many more likely exist that have yet to be discovered.75, 76 However, of those proteins that have been discovered and reported, several likely have a role in the direct dysfunction of neurons. GAPDH activity was significantly reduced after methylglyoxal treatment, which causes a compensatory increase of the toxic metabolite creating a pervasive, damaging cycle that leads to elevated levels of methylglyoxal and further reduction in GAPDH activity. Insulin and other key insulin-signaling molecules, such as insulin receptor substrate 1, were also susceptible to dicarbonyl glycation, which may alter the neurotrophic support for sensory neurons.79, 80 Methyglyoxal-modification of extracellular matrix reduced neurite outgrowth of sensory neurons, suggesting reactive dicarbonyls could impair the regenerative capacity of DRG neurons in diabetic neuropathy. Methylglyoxal has also been shown to alter the activity and expression of the 26S proteasome, as well as other chaperones involved with protein control.81, 82, 83 Although several proteins have been identified as targets for reactive dicarbonyls and explain various aspects of cellular dysfunction in diabetic neuropathy, proteins that are modified and accumulate in diabetic sensory neurons have yet to be determined.