**4.4 RAGE, endothelial dysfunction and insulin resistance**

Impaired insulin action, when assessed by fasting serum insulin levels or the homeostasis model assessment of insulin resistance (HOMA-IR) 92, is associated with atherosclerosis and an increased risk of myocardial infarction. Insulin resistance is associated with endothelial dysfunction 93 and may serve as a link between insulin resistance and atherosclerosis. Recent findings by Harja et al highlighted the involvement of RAGE in endothelial dysfunction 81. Endothelium-dependent vasorelaxation was tested in isolated mouse aortic rings from *apoE– /–* and *apoE–/–RAGE–/–* mice, and relaxation response to acetylcholine was significantly improved in the RAGE deficient mouse. Similarly, impaired endothelial function in diabetic obese mice was also shown to be mediated by AGEs/RAGE system, since blockade of AGE-RAGE interaction by soluble RAGE significantly improved endothelial function 94. Recent clinical observations by Linden et al 44 also implies AGEs/RAGE system is involved in impaired endothelial function in patients with chronic kidney diseases. Thus, not only by the interaction at the cellular signaling level, but RAGE appears to impair endothelial function and potentially blood flow in insulin target tissues, leading to insulin resistance in vivo.
