Pharmacological strategies to increase cGMP signaling may be achieved through two main routes: (1) direct activation of guanylate cyclase directly by augmentation of NO; and/or (2) decreasing cGMP hydrolysis through PDE5 inhibitors (sildenafil/ViagraTM, vardenafil/LevitraTM, tadalafil/CialisTM, avanafil/StendraTM), which is currently considered an important tool to treat endothelial dysfunction in DM [209,210,211]. This evidence concerns the gene PDE5A and diabetes mellitus.