AKR1B1 and Hyperglycemia: Although hypoxia is the main stimulatory factor of VEGF, several cytokines, growth factors, and other factors, out of which many are related to DN such as hyperglycemia, advanced glycation end products (AGEs), prostaglandins, mechanical stress, protein kinase C (PKC), reactive oxygen species (ROS), angiotensin II, and aldose reductase, also induce VEGF [27,28].