Abstract
BackgroundThis study aimed to examine the effects of l-citrulline (l-CIT) on low-grade inflammation (meta-inflammation) and insulin sensitivity in type 2 diabetes (T2D) patients since it has exhibited hypoglycemic and anti-inflammatory effects in most animal studies.MethodsIn this double-blind, placebo-controlled randomized clinical trial, 54 patients with T2D referred to specialized clinics of Tabriz University of Medical Sciences were assigned to l-CIT group (receiving orally one 3 g sachet of l-CIT daily before breakfast) or placebo group (receiving orally one 3 g sachet of microcrystalline cellulose daily before breakfast) for eight weeks. Serum levels of fasting blood glucose, hemoglobin A1c (HbA1c), CIT, monocyte chemoattractant protein 1 (MCP-1), interleukin-6 (IL-6), and toll-like receptor 4 (TLR-4) were determined. The quantitative insulin sensitivity check index (QUICKI) and homeostatic model assessment of β-cell function (HOMA-B) index were estimated at the baseline and post-intervention.ResultsNo significant difference was observed between the studied parameters at the baseline. l-CIT supplementation significantly reduced not only serum concentrations of fasting blood glucose but also HbA1c, serum IL-6 and TLR-4 levels in the l-CIT group (p < 0.05). Additionally, at the end of the study serum levels of CIT increased significantly in l-CIT group compared to the baseline and placebo group. Fasting blood glucose concentrations and HbA1c significantly decreased after the intervention compared to the placebo. There was no significant difference in serum IL-6, TLR-4, MCP-1 levels, as well as QUICKI and HOMA-B index between the two groups, even after adjusting for baseline variables and confounders.ConclusionsOur findings revealed that, although l-CIT supplementation significantly reduced fasting blood glucose concentrations, HbA1c and increased serum levels of CIT. It seems it could not significantly improve insulin sensitivity and meta-inflammation biomarkers. Additional studies with longer duration and different doses of l-CIT are required.Trial registration The protocol of this clinical trial is registered at the Iranian Registry of Clinical Trials (registration no: IRCT20100209003320N16 at www.irct.ir)
Highlights
This study aimed to examine the effects of l-citrulline (l-CIT) on low-grade inflammation and insulin sensitivity in type 2 diabetes (T2D) patients since it has exhibited hypoglycemic and anti-inflam‐ matory effects in most animal studies
Pregnancy, lactation, and post-menopause, those suffering from allergy, cancer, cardiovascular, inflammatory, intestinal, kidney, liver, and malabsorption diseases, hyperthyroidism/hypothyroidism, and polycystic ovary syndrome (PCOS) and followed weight-loss diets, receiving insulin, Sodium–glucose cotransporter-2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor analogues, nonsteroidal anti-inflammatory medications (NSAIDs), or any medication for lowering blood pressure, lipid, interacting with nitric oxide (NO) or any nutritional supplements during the last three months
No statistically significant effects of l-CIT supplementation were observed for the insulin sensitivity indices (HOMA-B and quantitative insulin sensitivity check index (QUICKI)), as well as meta-inflammatory biomarkers. The findings of this trial revealed that the supplementation with 3 g/day l-CIT for eight weeks significantly increased the serum levels of CIT and reduced fasting blood glucose concentrations, hemoglobin A1c (HbA1c) without any significant effects on QUICKI and Homeostatic model assessment of β-cell function index (HOMA-B), serum IL-6, monocyte chemoat‐ tractant protein 1 (MCP-1), and toll-like receptors (TLRs)-4 concentrations compared to the placebo in the patients with T2D
Summary
This study aimed to examine the effects of l-citrulline (l-CIT) on low-grade inflammation (meta-inflam‐ mation) and insulin sensitivity in type 2 diabetes (T2D) patients since it has exhibited hypoglycemic and anti-inflam‐ matory effects in most animal studies. Diabetes mellitus is a prevalent metabolic disorder which results in the abnormal function and insulin secretion [1]. In addition to the IR, meta-inflammation—a low-grade chronic metabolic inflammation—is crucial to T2D pathogenesis [6]. Chronic hyperglycemia and elevated free fatty acid (FFA) levels resulted in the IR and metainflammation [7]. The elevated FFA levels result in the IR by mitigating the phosphorylation of insulin receptor substrate-1 (IRS-1), stimulated by insulin, and its related phosphoinositide 3-kinase (PI3-K) activity [7, 8]. IR in fat tissue can itself increase the circulating levels of FFAs by increasing the lipolysis (defective cycle) [9]
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