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

Abstract

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.

Platelet Aggregation Increased by Advanced Glycated Hemoglobin

“…The chemistry of AGEs is not fully understood; in the meantime increased levels of circulating AGEs have been demonstrated in both animal and human diabetics [9]. AGE structures are associated with many pathophysiological abnormalities [10] as in diabetes and aging [11,12].…”

Glycated Albumin With Loss of Fatty Acid Binding Capacity Contributes to Enhanced Arachidonate Oxygenation and Platelet Hyperactivity: Relevance in Patients With Type 2 Diabetes

“…Several reports indicate that AGE products are able at least in vitro to induce activation of various cells including platelets (16,17). In addition to classical glycemic indices, several recent reports indicated that glycated albumin is a relevant and practical biomarker for the progression of diabetic atherosclerosis (18)(19)(20).…”

Association between advanced glycation end-products and functional performance in Alzheimer's disease and mixed dementia

“….................................................................................................................................................................................................................................................................................................................................................................................................................................................... In accordance with the results of this study, it would be interesting to investigate whether decline in functional mobility can be attenuated by reducing AGEs levels. Excessive elevation of glucose concentration, such as in DM, most likely accelerates the glycation of proteins (Ahmed and Thornalley, 2007;Rahmadi et al, 2011). Intensive glycaemic control may be a method to decrease AGEs formation.…”