# L-Citrulline: A Non-Essential Amino Acid with Important Roles in Human Health
## 7 Other Positive Effects of L-Citrulline
### L-Cittuline and Diabetes  
Endothelial cell dysfunction is the initial step in cardiovascular diseases such as hypertension and diabetes mellitus. The main causes of diabetic complications are alterations in vascular structures and functions, which is why preventing these complications is so important. Reduced availability of Arg to the endothelial nitric oxide synthase (eNOS o NOS3) was linked to vascular dysfunction in diabetes and several other diseases [58]. High plasma glucose level can lead to increased ROS and decreased NO bioavailability and also cause the development of diabetic atherosclerosis. NOS substrates can slow down endothelial senescence under high glucose through NO, possibly due to interference with the redox balance of endothelial cells [87]. Arg is the common substrate for both enzymes NOS3 and arginase, which therefore compete. Consequently, the activation of arginase enzyme decreases Arg availability for NOS3 and NO production in tissues as well as in cells [58]. Previous authors reported that the administration of CIT, normalize and ornithine in diabetic animals alleviated the hypertension associated with diabetes mellitus [91]. According to this, CIT and Arg plus CIT supplementation retarded high glucose-induced endothelial senescence [92]. Additionally, after 4 weeks of dietary supple mentation in drinking water with Arg (0.2%) or watermelon rich in CIT (63%) enhanced endothelium-dependent relaxation in Zucker diabetic fatty rats [93]. Moreover, in a study involving patients with type 2 diabetes mellitus and microvascular complications, inhibiting the arginase enzyme improved resistance and conduit artery endothelial function. The increased arginase activity decreases the bioavailability of Arg as a substrate of NOS, therefore reducing the production of NO, and this has also been shown to be linked to increased reactive oxygen species production [94]. This may be due to the fact that NOS produces superoxide when there is a deficit of substrate Arg, this phenomenon is known as \"eNOS uncoupling\", and further reduces the bioavailability of NO [28]. In addition, the inhibition of arginase can be carried out via direct or indirect mechanisms. The direct protective mechanism involves maintaining endothelial-dependent relaxation and generating NO, and the indirect mechanism is by inhibiting insulin resistance and hypertriglyceridemia [95]. On the other hand, in vivo experimental tests on mice demonstrated that Arg and CIT supplementation both enhanced the microcirculation in organs, through increased Arg availability and NO production; this was studied in conditions of acute Arg deficit, induced by the injection of the enzyme arginase [96]. However, [PERSON] et al. [97] reported that chronic Arg (1.5%) or CIT (1.66%) supplementation (in drinking water for 9 weeks) did not prevent or reduce renal injury in a model of type I diabetes in diabetic mice, despite greatly increasing kidney and plasma Arg levels. Finally, a recent systematic review concluded that CIT and watermelon extract may beneficially affect glycemic status and inflammation in diabetes mellitus, although studies on their antioxidant and hypolipidemic effects in diabetic patients are scarce [98].