Advanced Glycation End Products and Diabetes Mellitus: Mechanisms and Perspectives

Persistent hyperglycemic state in type 2 diabetes mellitus leads to the initiation and progression of non-enzymatic glycation reaction with proteins and lipids and nucleic acids. Glycation reaction leads to the generation of a heterogeneous group of chemical moieties known as advanced glycated end products (AGEs), which play a central role in the pathophysiology of diabetic complications. The engagement of AGEs with its chief cellular receptor, RAGE, activates a myriad of signaling pathways such as MAPK/ERK, TGF-beta, JNK, and NF-kappa B, leading to enhanced oxidative stress and inflammation. The downstream consequences of the AGEs/RAGE axis involve compromised insulin signaling, perturbation of metabolic homeostasis, RAGE-induced pancreatic beta cell toxicity, and epigenetic modifications. The AGEs/RAGE signaling instigated modulation of gene transcription is profoundly associated with the progression of type 2 diabetes mellitus and pathogenesis of diabetic complications. In this review, we will summarize the exogenous and endogenous sources of AGEs, their role in metabolic dysfunction, and current understandings of AGEs/RAGE signaling cascade. The focus of this review is to recapitulate the role of the AGEs/RAGE axis in the pathogenesis of type 2 diabetes mellitus and its associated complications. Furthermore, we present an overview of future perspectives to offer new therapeutic interventions to intervene with the AGEs/RAGE signaling pathway and to slow down the progression of diabetes-related complications.

Automated summary

Persistent hyperglycemia in type 2 diabetes mellitus triggers a glycation reaction, resulting in the formation of AGEs. Binding of AGEs with its receptor RAGE activates various signaling pathways, leading to oxidative stress, inflammation, compromised insulin signaling, metabolic disturbances, pancreatic beta cell toxicity, and epigenetic modifications. This review summarizes the sources of AGEs, their role in metabolic dysfunction, and the AGEs/RAGE signaling cascade in type 2 diabetes mellitus and its associated complications.