The effect of L-citrulline supplementation on nutrirtional, metabolic, oxidative and inflammatory status and serum levels of L-citrulline and NOx in type 2 diabetes patients: A randomized controlled clini-cal trial

Abstract

Background: Diabetes mellitus is the most common metabolic disease and a major cause of death in in the world. L-citrulline- a non-essential alpha amino acid- is a precur-sor of L-arginine and thus the production of nitric oxide. Results of animal studies have indicated positive effects of L-citrulline on inflammatory and metabolic pathways of T2DM. Therefore, this study was designed to determine the effect of L-citrulline sup-plementation on nutritional, metabolic, oxidative and inflammatory status and serum levels of L-citrulline and nitrate/nitrite (NOx) in patients with T2DM. Methods: In this double-blind randomized controlled clinical trial, 45 patients with type 2 diabetes enrolled (23 in the L-citrulline group (receiving a 3-gram sachet of L-citrulline) and 22 in the placebo group (receiving a 3-gram sachet of microcrystalline cel-lulose dissolved in a glass of water before breakfast for eight weeks). All subjects were asked to follow a healthy diet. Demographic and 3-day food record questionnaires were completed and anthropometric indices were measured at the beginning and end of the study. At the beginning and end of the study, intravenous fasting blood sample was taken and glycemic indices, lipid profile, inflammatory markers (high sensitive C-reactive protein (hs-CRP), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels), oxidative stress markers (total antioxidant capacity (TAC), malondialdehyde (MDA) levels, the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx)) in whole blood, serum levels of citrulline and nitrate and nitrite (NOx) were as-sessed. Results: At the end of the study, supplementation with L-citrulline significantly in-creased serum levels of citrulline (P = 0.006) and NOx (P < 0.001) compared with the placebo group. There was no significant difference in dietary intake and anthropometric indices (weight, BMI and waist circumference) inter- and intra-groups. L-citrulline sup-plementation significantly reduced serum concentrations of glucose (P = 0.032), hemo-globin A1c (P = 0.001), insulin (P = 0.025) and insulin resistance index (HOMA-IR) (P = 0.037) but it did not affect serum levels of total cholesterol and low density lipopro-tein cholesterol in the L-citrulline group. Serum triglyceride levels significantly de-creased (P = 0.027) while serum high density lipoprotein cholesterol levels increased (P < 0.001). However, there was no significant difference between the two groups. L-citrulline supplementation significantly increased serum TAC (P < 0.001) and reduced serum MDA levels (P < 0.001) compared with the placebo group. However, the activity of SOD and GPx enzymes were not influenced. In addition, L-citrulline supplementa-tion significantly decreased TNF-α (P = 0.036) and hs-CRP (P = 0.027) levels compared with the placebo group. Despite a significant decrease in serum concentrations of IL-6 in the L-citrulline group (P < 0.001), the difference between the two groups was not statis-tically significant. Conclusion: L-citrulline supplementation resulted in increased serum levels of L-citrulline and NOx and the improvement of some glycemic, inflammatory and oxidative markers and in patients with T2DM.