TNF and endothelial dysfunction: Several underlying causes of diabetic endothelial dysfunction in the model of acetylcholine-induced vascular relaxation are known: (1) production of reactive oxygen species (ROS) by hyperglycemia per se, which reduces nitric oxide (NO) bioavailability; (2) higher levels of plasma TNF-α which induce vascular inflammation; (3) TNF-α, which directly induces endothelial dysfunction via NF-κB activation, impairment of eNOS expression, and ROS formation; and (4) the AGEs–RAGE axis [30,31,32,33,34,35,36].