Glycation and diabetes: The RAGE connection

The hyperglycaemic state seen in diabetes mellitus is associated with the development of diabetes-specific microvascular complications and accelerated macrovascular disease. Evidence implicates the formation and subsequent effects of advanced glycation end-products (AGEs) as a contributing cause. AGEs exert their effects through interaction with the Receptor for AGE (RAGE) which upregulates expression of the receptor and induces a cascade of cytotoxic pathways. Accumulation of AGE/RAGE can be seen at sites of vascular disease in both animal models of diabetes and human diabetic subjects. Blockade of RAGE in animal models of diabetes suppresses development of dysfunction in the vasculature and atherosclerosis development. Genetic studies of RAGE reveal that a number of allelic variants of RAGE occur in key protein and regulatory domains. A Gly to Ser change at position 82 and two 5′ flanking polymorphisms at position -374 and -429 lead to altered function and expression of RAGE which may impact on diabetic vascular disease development. Therapy aimed to block RAGE upregulation may prove to be useful in treating individuals with diabetic vascular disease.