br Advanced Glycation Endproducts As glucose

Advanced Glycation Endproducts As glucose levels rise within sensory neurons as a result of hyperglycemia, normal metabolic pathways become overwhelmed and excess glucose is shunted into other ancillary pathways that, under these conditions, become damaging. One consequence of hyperglycemia is the increased and accelerated production of advanced glycation endproducts (AGEs) in tissues where damage results in secondary complications, including peripheral nerves. Importantly, AGEs have been shown to have a role in the pathogenesis of diabetic neuropathy. AGEs are a heterogeneous group of molecules that form from the nonenzymatic addition of sugar moieties onto arginine and lysine residues of proteins, free amino groups on lipids, or guanine nucleic acids. The process of nonenzymatic glycation was first described by L.C. Maillard in the early 1900s, and even at that time, he speculated it may be an important process in diabetes. It has subsequently become apparent that nonenzymatic glycation and AGEs have a role in many disease processes, such as aging, neurological disorders, and diabetic complications. The classic AGE pathway involves the rearrangement of glucose or another reducing sugar, such as fructose, galactose, mannose, or ribose, that reacts with a free amino group of a protein, which forms a Schiff BI-D1870 (Fig 1). The Schiff base is highly unstable and degrades into the Amadori product or fructosamine. Fructosamine is relatively stable, although levels tend to fluctuate with glucose concentrations. The most well-known example of an Amadori product is hemoglobin A1c (HbA1c), a naturally occurring modification to the N-terminal valine amino group of the β chain of hemoglobin. HbA1c is elevated in diabetic patients and gives an indication of glucose levels over the previous 2–3 months. It is often used to monitor glucose control and has value at predicting risk of complications.9, 38 With further rearrangement, oxidation, and elimination, fructosamine produces an AGE. Considerable progress has been made in understanding that AGEs form from specific metabolites despite the complexity of the glycation process. Although intermediate steps in the glycation pathway are reversible, AGE formation is irreversible and causes modifications that result in both protease-resistant, cross-linked and non–cross-linked proteins.39, 40 Besides monosaccharides, reactive dicarbonyls or α-oxoaldehydes contribute to the production of AGEs. Reactive dicarbonyls, such as 3-deoxyglucose, glyoxal, and methylglyoxal, are highly potent and reactive species that can also modify proteins, lipids, and nucleic acids and may contribute more significantly in the glycation process than the classic pathway described above (Fig 1). In fact, reactive dicarbonyls are 20,000-fold more reactive than glucose. Consequently, reactive dicarbonyls have gained increasing acceptance as one of the main mechanisms that drives the production of AGEs, produces carbonyl stress, and underlies the development of diabetic complications. As a result of a combination of increased flux through glycolysis and reduced activity of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), both glyceradehyde 3-phosphate and dihydroxyacetone phosphate (DHAP) build up in the neuron. Under normal conditions, low levels of these metabolites are converted to methylglyoxal. However, under hyperglycemic conditions, concentrations of methylglyoxal increase within the neuron as a result of the nonezymatic breakdown of these 2 glycolytic intermediates.42, 43 Elevated levels of methylglyoxal as well as other sugars, such as fructose, lead to the formation of AGEs. AGEs modify cellular components, signal through the receptor for advanced glycation endproducts (RAGE), and compromise normal neuronal function. The longstanding view of glycation as a relatively long process that only resulted in AGE accumulation on long-lived extracellular proteins was revolutionized with the discovery of dicarbonyl metabolites. Methylglyoxal and other α-oxoaldehydes form inside cells over a relatively short time period as a by-product of many metabolic pathways. Methylglyoxal is formed from spontaneous decomposition of triosephosphates, DHAP and glyceraldehyde-3-phosphate, fragmentation of other sugars, and amino acid and ketone body degradation.45, 46, 47 Glyoxal is also a consequence of degradation of saccharides, but also of lipid peroxidation and degradation of glycated proteins. Cellular concentrations of methylglyoxal and glyoxal range from 1 to 5 μM and from 0.1 to 1 μM, respectively. The biogenesis of 3-deoxyglucose results from the breakdown of fructose-3-phosphate from the polyol pathway. It is important to note that all of these metabolic processes are enhanced in diabetes mellitus, which leads to a significant increase in the production of reactive dicarbonyls and AGEs.