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Diabetes, advanced glycation endproducts and vascular disease

Biologie Vasculaire et Cellulaire, UFR - Lariboisie`re - Saint Louis et INTS, Paris, France

Pierre-Jean Guillausseau

Service de Médecine Interne 2, Hôpital Lariboisière et FacultédeMédecine Lariboisie`re - Saint Louis, Université Paris VII, France

The high incidence of vascular complications in patients with diabetes mellitus remains incompletely understood. Several metabolic or endocrine abnormalities have been postulated as possible triggers for micro and macroangiopathies. This review article focuses on the consequences of hyperglycemia, leading to the formation of advanced glycation endpro-ducts (AGE), on vascular function. Advanced glycation endproducts are the product of the binding of aldoses onto free amino groups of proteins or lipoproteins, which, after molecular rearrangement, result in a class of molecules of a brown color and specific fluorescence. Different cell membrane proteins have been shown to bind AGE and the best characterized receptor for AGE has been named RAGE. The AGE receptor is present on different cell types including endothelial cells, smooth muscle cells, lymphocytes and monocytes.

Experimental studies have revealed that the binding of AGE to RAGE produces an activation of monocytes and endothelial cells. Activated endothelial cells produce interleukin and express vascular cell adhesion molecule and tissue factor. Advanced glycation endproducts, when infused into animals, induce an increase in vascular permeability. The blockade of RAGE by specific antibodies corrects the hypermeability observed in diabetic animals.

The prevention of AGE formation by aminoguanidine treatment improves the microvascular lesions found in diabetic animals either in the retina or the glomerus. The infusion of recombinant RAGE in diabetic animals corrects hyperpermeability. The colocalization of RAGE and AGE at the microvascular site of the injury suggests that their interaction may play a significant role in the pathogenesis of diabetic vascular lesions.

Key Words: AGE receptors • angiopathy • diabetes mellitus • glycation

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