Figure 2. RAGE and its ligands – a self-perpetuating axis of glucose and inflammatory stress in diabetic tissues.
In diabetic tissues vulnerable to complications, we propose that hyperglycemia-mediated formation of AGEs is an early step; the slow but inexorable accumulation of AGEs ultimately achieves a critical threshold of ligand capable of activation of RAGE. Once RAGE is activated, a seminal event is attraction of immune cells to AGE-laden foci. We predict that these immune cells become activated and during that process release pro-inflammatory RAGE ligands such as S100/calgranulins and HMGB1. Then, vascular-immune cell interactions via mac-1 further propagate inflammation, leading to vascular perturbation and, ultimately, end-organ damage in diabetes.