AGEs accumulation with vascular complications, glycemic control and metabolic syndrome: A narrative review

Background: Multiple pathogenetic mechanisms are involved in the genesis of various microvascular and macrovascular complications of diabetes mellitus. Of all these, advanced glycation end products (AGEs) have been strongly implicated.Objectives: The present narrative review aims to summarize the available literature on the genesis of AGEs and their potential role in the causation of both micro-and macrovascular complications of diabetes mellitus.Results: Uncontrolled hyperglycemia triggers the formation of AGEs through non-enzymatic glycation reactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs accumulate in bloodstream and bodily tissues under chronic hyperglycemia. AGEs create irreversible cross-linkages of various intra-and extracellular molecules and activate the receptor for advanced glycation end products (RAGE), which stimulates downstream signaling pathways that generate reactive oxygen species (ROS) and contribute to oxidative stress. Additionally, intracellular glycation of mitochondrial respiratory chain proteins by AGEs contributes to the further generation of ROS, which, in turn, sets a vicious cycle that further promotes the production of endogenous AGEs. Through these pathways, AGEs play a principal role in the pathogenesis of various diabetic complications, including diabetic retinopathy, nephropathy, neuropathy, bone disease, atherosclerosis and non-alcoholic fatty liver disease. Multiple clinical studies and meta-analyses have revealed a positive association between tissue or circulating levels of AGEs and development of various diabetic complications. Besides, exogenous AGEs, primarily those derived from diets, promote insulin resistance, obesity, and metabolic syndrome.Conclusions: AGEs, triggered by chronic hyperglycemia, play a pivotal role in the pathogenesis of various complications of diabetes mellitus.

Automated summary

Various pathogenetic mechanisms are involved in the complications of diabetes mellitus, with advanced glycation end products (AGEs) playing a crucial role. Chronic hyperglycemia triggers the formation of AGEs, which accumulate in the bloodstream and tissues and lead to the activation of receptor for advanced glycation end products (RAGE). AGEs are involved in the pathogenesis of diabetic complications and their levels are positively associated with the development of these complications. Exogenous AGEs derived from diets also contribute to insulin resistance, obesity, and metabolic syndrome.