L-Citrulline Supplementation Increases Plasma Nitric Oxide Levels and Reduces Arginase Activity in Patients With Type 2 Diabetes

Abstract

Type 2 diabetes mellitus (T2DM) is becoming a major contributor to cardiovascular disease. One of the early signs of T2DM associated cardiovascular events is the development of vascular dysfunction. This dysfunction has been implicated in increasing the morbidity and mortality of T2DM patients. One of the important characteristics of vascular dysfunction is the impaired ability of endothelial cells to produce nitric oxide (NO). Additionally, decreases in the availability of NO is also a major contributor of this pathology. NO is produced by the activity of endothelial NO synthase (eNOS) on its substrate, L-arginine. Reduced availability of L-arginine to eNOS has been implicated in vascular dysfunction in diabetes. Arginase, which metabolizes L-arginine to urea and ornithine, competes directly with NOS for L-arginine. Hence, increases in arginase activity can decrease arginine levels, reducing its availability to eNOS and decreasing NO production. Diabetes has been linked to elevated arginase and associated vascular endothelial dysfunction. We aimed to determine levels of plasma NO and arginase activity in (T2DM) patients and the effects of L-citrulline supplementation, a natural arginase inhibitor, on inhibiting arginase activity in these patients. Levels of arginase correlated with HbA1c levels in diabetic patients. Twenty-five patients received L-citrulline supplements (2000 mg/day) for 1 month. Arginase activity decreased by 21% in T2DM patients after taking L-citrulline supplements. Additionally, plasma NO levels increased by 38%. There was a modest improvement on H1Ac levels in these patients, though not statistically significant. The effect of L-citrulline on arginase activity was also studied in bovine aortic endothelial cells (BAECs) grown in high glucose (HG) conditions. HG (25 mM, 72 h) caused a 2-fold increase in arginase activity in BAECs and decreased NO production by 30%. L-citrulline (2.5 mM) completely prevented the increase in arginase activity and restored NO production levels. These data indicate that L-citrulline can have therapeutic benefits in diabetic patients through increasing NO levels and thus maintaining vascular function possibly through an arginase inhibition related pathway.

Effects of L-Citrulline Supplementation and Aerobic Training on Vascular Function in Individuals with Obesity across the Lifespan

“…These findings suggest that L-Cit improves the L-Arg-NO pathway in children with MELAS syndrome. in T2D patients [107]. Thus, L-Cit supplementation can be a viable therapeutic strategy to improve obesity and hyperglycemia-induced endothelial function by increasing L-Arg and NO bioavailability in middle-aged adults [22,23,26,43].…”

“…Few studies have evaluated the metabolic effects of L-Cit in adult humans. L-Cit supplementation has improved serum levels of NO, lipids (triglyceride, HDL cholesterol), glucose control (insulin, glucose, glycated hemoglobin (HbA1c), HOMA-IR), and inflammation (TNF-α and C-reactive protein) in patients with obesity and T2D [107,122]. Further studies are required to evaluate the effects of L-Cit supplementation on lipid and glucose metabolism in individuals with obesity including children and adolescents.…”

“…dren and adolescents with obesity with lower NO production and endothelial dysfunction [102,103]. L-Cit supplementation has also demonstrated to improve glucose control [107,122], muscle protein synthesis [27], and body composition (lean mass and fat mass) [116] (Figure 3). The combination of aerobic exercise training and L-Cit supplementation on metabolic and cardiovascular parameters in obesity has only been studied in adults (Table 4).…”

“…L-Cit supplementation (5.8 g/day) improves macrovascular function by activation of the L-Arg-NO pathway [ 26 ]. Similarly, L-Cit supplementation (2 g/day) for 1 month increased plasma NO levels via inhibition of arginase activity in T2D patients [ 107 ]. Thus, L-Cit supplementation can be a viable therapeutic strategy to improve obesity and hyperglycemia-induced endothelial function by increasing L-Arg and NO bioavailability in middle-aged adults [ 22 , 23 , 26 , 43 ].…”

“…L-Cit supplementation increases the bioavailability of L-Arg and NO to enhance vasodilation [ 22 , 23 , 26 ], improve arterial stiffness, and regulate blood pressure by having an antihypertensive effect in adults [ 23 , 24 ], and may improve endothelial function in children and adolescents with obesity with lower NO production and endothelial dysfunction [ 102 , 103 ]. L-Cit supplementation has also demonstrated to improve glucose control [ 107 , 122 ], muscle protein synthesis [ 27 ], and body composition (lean mass and fat mass) [ 116 ] ( Figure 3 ). The combination of aerobic exercise training and L-Cit supplementation on metabolic and cardiovascular parameters in obesity has only been studied in adults ( Table 4 ).…”