Glycation End-Products and their Receptors: Pathophysiology and Therapeutic Targeting in Diabetes Mellitus

Abstract

Diabetes mellitus (DM) compromises cell metabolism and function in many organs, resulting in increased risks of complications in many organs such as kidney, nervous system, eye, and fragility fractures. Advanced glycation end products (AGEs) are chemical moieties produced during long-term hyperglycemia; they interact with the specific receptors for AGEs (RAGEs) and make a meaningful contribution to cellular metabolism and/or alteration of their functions. Searches in PubMed using the keywords "advanced glycation end product "RAGE", "sRAGE", "DM", and "complications” were made to reveal some of the clinical outcomes of DM in cellular metabolism and organ function through the AGE-RAGE signaling pathway. All published experimental and clinical studies were included in tables. The AGE-RAGE signaling is involved in diabetic complications such as nephropathy, neuropathy, retinopathy, and osteopathy. Some clinical results in diabetic patients could be potentially attributed to AGE-RAGE signaling consequences. However, the AGE-RAGE signaling pathway has some helpful roles in many tissues, including an increase in osteogenic function. Soluble RAGE (sRAGE), as a ligand decoy, may increase in either condition of RAGE production or destruction, and then it cannot always reflect the AGE-RAGE signaling. Although various medicines are capable to target the AGE-RAGE axis. They can also limit the associated damaging consequences. Recombinant sRAGE can block the AGE-RAGE signaling pathway; however, it is associated with some limitations such as accessibility to AGEs, increase in other RAGE ligands, and a long half-life (24 hours). It is associated with losing the beneficial effect of AGE/RAGE. As a result, sRAGE is not a helpful marker to assess the activity of the RAGE signaling pathway. The recombinant sRAGE cannot be translated into clinical practice due to its limitations.