https://onlinelibrary.wiley.com/doi/pdf/10.1002/1529-0131%28199809%2941%3A9%3C1521%3A%3AAID-ART2%3E3.0.CO%3B2-A

Antineutrophil cytoplasmic antibodies

Glycation is a major cause of spontaneous damage to proteins in physiological systems. This is exacerbated in diabetes as a consequence of the increase in glucose and other saccharides derivatives in plasma and at the sites of vascular complications. Protein damage by the formation of early glycation adducts is limited to lysine side chain and N-terminal amino groups whereas later stage adducts, advanced glycation endproducts (AGEs), modify these and also arginine and cysteine residues. Metabolic dysfunction in vascular cells leads to the increased formation of methylglyoxal which adds disproportionately to the glycation damage in hyperglycaemia. AGE-modified proteins undergo cellular proteolysis leading to the formation and urinary excretion of glycation free adducts. AGEs may potentiate the development of diabetic complications by activation of cell responses by AGE-modified proteins interacting with specific cell surface receptors, activation of cell responses by AGE free adducts, impairment of protein-protein and enzyme-substrate interactions by AGE residue formation, and increasing resistance to proteolysis of extracellular matrix proteins. The formation of AGEs is suppressed by intensive glycaemic control, and may in future be suppressed by thiamine and pyridoxamine supplementation, and several other pharmacological agents. Increasing expression of enzymes of the enzymatic defence against glycation provides a novel and potentially effective future therapeutic strategy to suppress protein glycation.

Advanced glycation endproducts: what is their relevance to diabetic complications?

Nonenzymatically glycated human serum albumin and glycated poly-lysine(Lys) in vitro brought about the reduction of nitroblue tetrazolium and ferricytochrome c at pH 9.06 and pH 7.8, respectively. This reduction was inhibited partially by superoxide dismutase (SOD). Glycated poly-Lys caused the oxidation of NADH in the presence of LDH at pH 7.0 which was completely inhibited by SOD. Glycated material was found to function both as a reductant and an oxidant. The reactivity of glycated material is discussed and a possible mechanism by which superoxide is produced is proposed. Results may give a clue to diabetic complications.

Superoxide production from nonenzymatically glycated protein

Antineutrophil cytoplasmic antibodies.

Glycation is the nonenzymatic reaction of glucose, alpha-oxoaldehydes, and other saccharide derivatives with proteins, nucleotides, and lipids. Early glycation adducts (fructosamines) and advanced glycation adducts (AGEs) are formed. "Glycoxidation" is a term used for glycation processes involving oxidation. Sural, peroneal, and saphenous nerves of human diabetic subjects contained AGEs in the perineurium, endothelial cells, and pericytes of endoneurial microvessels and in myelinated and unmyelinated fibres localized to irregular aggregates in the cytoplasm and interstitial collagen and basement membranes. Pentosidine content was increased in cytoskeletal and myelin protein extracts of the sural nerve of human subjects and cytoskeletal proteins of the sciatic nerve of streptozotocin-induced diabetic rats. AGEs in the sciatic nerve of diabetic rats were decreased by islet transplantation. Improved glycemic control of diabetic patients may be expected to decrease protein glycation in the nerve. Protein glycation may decrease cytoskeletal assembly, induce protein aggregation, and provide ligands for cells surface receptors. The receptor for advanced glycation and products (RAGE) was expressed in peripheral neurons. It is probable that high intracellular glucose concentration is an important trigger for increased glycation, leading to increased formation of methylglyoxal, glyoxal, and 3-deoxyglucosone that glycate proteins to form AGEs intracellularly and extracellularly. Oxidative stress enhances these processes and is, in turn, enhanced by AGE/RAGE interactions. An established therapeutic strategy to prevent glycation is the use of alpha-oxoaldehyde scavengers. Available therapeutic options for trial are high-dose nicotinamide and thiamine therapies to prevent methylglyoxal formation. Future possible therapeutic strategies are RAGE antagonists and inducers of the enzymatic antiglycation defense. More research is required to understand the role of glycation in the development of diabetic neuropathy.

Glycation in diabetic neuropathy: characteristics, consequences, causes, and therapeutic options.

Role of advanced glycation end-products (AGE) in late diabetic complications.

Advanced glycation end-products (AGEs) are irreversible compounds which, by abnormally accumulating over proteins as a consequence of diabetic hyperglycaemia, can damage tissues and thus contribute to the pathogenesis of diabetic complications. This study was performed to evaluate whether restoration of euglycaemia by islet transplantation modifies AGE accumulation in central and peripheral nervous tissue proteins and, as a comparison, in proteins from a non-nervous tissue. Two groups of streptozotocin diabetic inbred Lewis rats with 4 (T1) or 8 (T2) months disease duration were grafted into the liver via the portal vein with 1200-1500 islets freshly isolated from normal Lewis rats. Transplanted rats, age-matched control and diabetic rats studied in parallel, were followed for a further 4-month period. At study conclusion, glycaemia, glycated haemoglobin and body weight were measured in all animals, and an oral glucose tolerance test (OGTT) performed in transplanted rats. AGE levels in cerebral cortex, spinal cord, sciatic nerve proteins and tail tendon collagen were measured by enzyme-linked immunosorbent assay (ELISA). Transplanted animal OGTTs were within normal limits, as were glycaemia and glycated haemoglobin. Diabetic animal AGEs were significantly higher than those of control animals. Protein AGE values were reduced in many transplanted animals compared to diabetic animals, reaching statistical significance in spinal cord (P < 0.05), sciatic nerve (P < 0.02) and tail tendon collagen (P < 0.05) of T1 animals. Thus, return to euglycaemia following islet transplantation after 4 months of diabetes with poor metabolic control reduces AGE accumulation rate in the protein fractions of the mixed and purely peripheral nervous tissues (spinal cord and sciatic nerve, respectively). However, after a double duration of bad metabolic control, a statistically significant AGE reduction has not been achieved in any of the tissues, suggesting the importance of an early therapeutic intervention to prevent the possibly pathological accumulation of AGEs in nervous and other proteins.

Reduction of advanced glycation end‐product (AGE) levels in nervous tissue proteins of diabetic Lewis rats following islet transplants is related to different durations of poor metabolic control

Antineutrophil Cytoplasmic Antibodies are Present in Long Standing Type 1 Diabetics but do not Correlate with Selective Proteinuria

Formation and ways of detecting advanced glycation end-products in isolated human glomerular basement membrane and human serum albumin nonenzymatically glycated in vitro.

Maria Grazia De Rossi

Papers

Role of advanced glycation end-products (AGE) in late diabetic complications.

Reduction of advanced glycation end‐product (AGE) levels in nervous tissue proteins of diabetic Lewis rats following islet transplants is related to different durations of poor metabolic control

Antineutrophil Cytoplasmic Antibodies are Present in Long Standing Type 1 Diabetics but do not Correlate with Selective Proteinuria

Formation and ways of detecting advanced glycation end-products in isolated human glomerular basement membrane and human serum albumin nonenzymatically glycated in vitro.