Third, decreased NOS activity and production of NO from L-arginine as well as increased arginase activity, which leads to decreased L-arginine bioavailability and NO synthesis via NOS, are other disrupted pathways in NO homeostasis in diabetic conditions [32]; finally, since activation of NOS is regulated by insulin and the Akt signaling pathway, impaired insulin secretion and insulin resistance due to diabetes could affect NO synthesis [33] (Fig. 1). Here, INS is linked to diabetes mellitus.