Session: S50-Molecular Basis of Diabetes Complications
Room 303 (Moscone Center)
The consequences of chronic hyperglycemia are insidious and among these is the accelerated formation of the products of nonenzymatic glycation and oxidation of proteins, the advanced glycation endproducts or AGEs. Extensive data link the accumulation of AGEs in multiple tissues in diabetic human subjects and animal models to the presence of complications. AGEs exert their effects in part by receptor-dependent mechanisms; the principal AGE receptor is the receptor for AGE or RAGE. RAGE is a signal transduction receptor of the immunoglobulin superfamily. RAGE is upregulated in macro- and microvascular tissues vulnerable to complications in human subjects. Using genetic modification strategies and administration of RAGE antagonists, multiple laboratories have shown protection against complications in animal models. The discovery that RAGE bound inflammatory ligands such as S100/calgranulins and high mobility group box 1 (HMGB1) suggested that inflammatory and oxidative stress cues participated in diabetic complications. Recently, we have shown that the cytoplasmic domain of RAGE binds to the formin molecule mDia1 and that this interaction is essential for RAGE signaling. Emerging data reveal that diabetic mice devoid of mDia1 are protected against cardiac complications of diabetes. Work is underway to develop antagonists of RAGE cytoplasmic domain-mDia1 binding as a novel strategy to suppress diabetes complications.