SMAD2 and diabetes mellitus: Chronic activationof RAGE has been shown to be involved in mediating the pathophysiologicalcardiac remodeling observed in a number of diseases, including heartfailure, diabetes, and obesity.3,43 Putatively, RAGE signalingacts through phosphorylation of p38 MAPK and NF-κB activation,44 phosphorylation of SMAD2/3,45 and phosphorylation of STAT318 to activate fibroblasts and increase the production of inflammatoryfactors.