• Metformin improved EDV in vascular tissue from diabetic mice.• A 3 hour exposure to 50 μM metformin reduced high-glucose induced reduction in phosphorylate in eNOS and Akt. Data also suggest effects of metformin are partially dependent on AMPK activation.• Collectively the data from studies of metformin and endothelial function indicate: a. Metformin protects endothelial function in patients with diabetes and• b. pre-clinical data supports a direct protective effect on the endothelium via reducing oxidative stress and hyperglycemia-induced endothelial cell senescence. The gene discussed is NOS3; the disease is Hyperglycemia.