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Background  This 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.    Methods  In 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.    Results  No 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.    Conclusions  Our 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 )

diabetology and metabolic syndrome

The effects of citrulline supplementation on meta-inflammation and insulin sensitivity in type 2 diabetes: a randomized, double-blind, placebo-controlled trial