Diabetes mellitus and pre-diabetes are prevalent endocrine disorders associated with substantial morbidity and premature mortality. Vitamin K is known to have several beneficial effects on complications of diabetes and pre-diabetes. However, systematic consolidation of evidence is required to quantify these effects in order to inform clinical practice and research. A systematic search in PubMed, Scopus, Embase, ProQuest, and Google Scholar databases was undertaken from database inception up to October 2018 to evaluate functional roles of different forms of vitamin K on diabetes and pre-diabetes. From 3,734 identified records, nine articles met the inclusion criteria and were evaluated. Vitamin K supplementation was found to be associated with significant reductions in blood glucose (six studies), increased fasting serum insulin (four studies), reduced hemoglobin A1c (three studies), reduced homeostatic model assessment-insulin resistance index (HOMA-IR

This study investigated the impact of L-citrulline on glucose homeostasis, lipid profile, and inflammatory factors in overweight and obese patients with type 2 diabetes (T2D). In total, 54 participants with T2D were assigned to L-citrulline (3 g/day L-citrulline) or placebo groups and tested for 8 weeks. Serum levels of insulin, fasting glucose, hemoglobin A1c (HbA1c), lipid profile, tumor necrosis factor-α (TNF-α), highsensitivity C-reactive protein (hs-CRP), and L-citrulline were measured pre-and post-intervention. Totally, 45 patients were enrolled in the research. L-citrulline supplementation decreased serum levels of insulin (p = .025), glucose (p = .032), HbA1c (p = .001), HOMA-IR (p = .037), TNF-α (p = .036), and hs-CRP (p = .027) significantly. At the end of the study, despite the significant decrease in serum levels of triglyceride (p = .027) and the increase in high-density lipoprotein cholesterol levels (p < .001) in the L-citrulline group, no significant differences were found for these parameters between the groups. Moreover, no significant inter-and intra-group changes were observed for dietary intakes, anthropometric indices, total and lowdensity lipoprotein cholesterol levels (p > .05). In conclusion, L-citrulline supplementation might improve glucose homeostasis, some lipid factors and inflammatory markers in overweight and obese patients with T2D.

Background: Type 2 diabetes mellitus (T2DM) is a prevalent disorder which accounts for 90-95% of diabetic patients. The aim of this study was to assess the effects of menaquinone (MK-7) supplementation on glycemic indices, anthropometric indices and lipid profile, among patients with T2DM. Methods: In this double-blind placebo-controlled randomized clinical trial, 60 men and women with T2DM were allocated equally into either the MK-7 (200 µg/day) or the placebo group. Physical activity level and dietary intake were assessed using the international physical activity questionnaire-short form (IPAQ-SF) and a 3-day food record, pre-and post-intervention. Anthropometric measures, blood pressure, glycemic indices and lipid profile including fasting blood sugar (FBS), hemoglobin A1c (HBA1C), fasting insulin (FI), homeostatic model assessment insulin resistance index (HOMA-IR), triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) were measured at baseline and after twelve weeks. Results: Forty-five patients completed the trial. There were no significant between-group differences for calorie intake, macronutrient intake, physical activity level or anthropometric measures at baseline and at the end of the study. Dietary vitamin K intake increased significantly at the end of the study in the MK-7 (p: 0.02) and placebo (p: 0.001) groups, but intergroup differences were not significant (p: 0.86). FBS (p: 0.01), HbA1c (p: 0.002), fasting insulin (p: 0.01) and HOMA-IR (p: 0.007) decreased significantly in the MK-7 group. Furthermore, after adjustment for the baseline values and changes of vitamin K intake at the end of study, FBS and HbA1C showed significant intergroup changes, and they were significantly lower in the MK-7 group compared to the placebo group. Lipid profile (TG, TC, LDL-C, HDL-C and LDL-C/HDL-C) did not change significantly within or between groups. Conclusion: MK-7 supplementation seems to be effective in the improvement of glycemic indices, but not the lipid profile of patients with T2DM. Clinical Trial Registration: The present study was prospectively registered at the Iranian Registry of Clinical Trials on May 2019 (ID: IRCT20100123003140N22).

Objective Diabetes mellitus is a prevalent endocrine disorder worldwide. Citrulline is an α‐amino acid, which is abundant in watermelon, and a precursor of arginine and nitric oxide. Decreased bioavailability of nitric oxide is associated with insulin resistance. The present systematic review focused on the existing evidence of citrulline and watermelon extract effects on metabolic and inflammatory parameters in diabetes mellitus. Methods A systematic search of the databases PubMed, Scopus, EMBASE, ProQuest and Google Scholar was conducted for relevant papers published from inception until October 2018. All clinical trials, animal and in vitro studies published in the English language that assessed the role of citrulline and watermelon extract on diabetes mellitus, were eligible. Studies providing inadequate information were excluded. Results Out of 1262 articles we found, only eight articles met the inclusion criteria for analysis. In three studies an increase in the synthesis of nitric oxide was reported with citrulline and watermelon extract supplementation. Four studies showed a significant reduction in blood glucose after supplementation with watermelon extract, and two studies reported a decrease in a number of inflammatory biomarkers following citrulline supplementation. Although citrulline intake caused a significant reduction in HOMA‐IR in one study, inconsistent results were revealed on the effects of citrulline and watermelon extract on insulin levels and lipid profile. Conclusion Citrulline and watermelon extract could improve nitric oxide synthesis, glycaemic status and inflammation in diabetes mellitus. However, further studies are required to shed light on the underlying mechanisms.

Background The pathogenesis of diabetes is accompanied by oxidative stress. Citrulline can be considered as a potent antioxidant. The present study aimed to examine the effects of citrulline supplementation on the status of oxidative stress and serum levels of nitrite/nitrate (NOx) in patients suffering from type 2 diabetes (T2DM). Methods The present study comprises a double‐blind placebo‐controlled randomised clinical trial. The study subjects include 54 patients with T2DM chosen from specialised clinics of Tabriz University of Medical Sciences. The patients were allocated to one of the placebo or intervention groups. The patients in the placebo and the intervention group received one sachet of microcrystalline cellulose or l‐citrulline (3 g), respectively, every day for 2 months. Malondialdehyde (MDA), glutathione peroxidase (GPx), total antioxidant capacity (TAC), superoxide dismutase (SOD), serum levels of fasting blood sugar (FBS), citrulline and NOx were assessed before and after the intervention. Results Forty‐five patients completed the trial. Significant decreases were found in serum levels of FBS and MDA. Serum levels of TAC, citrulline and NOx in the intervention group increased compared to those of the placebo group, after adjusting the data for the baseline values and confounders. Differences between and within the two groups were statistically nonsignificant for GPx and SOD at the end of the study. Body mass index and energy intake were not changed significantly after the intervention. Conclusions The results of the present study show the positive effects of citrulline supplementation with respect to attenuating FBS levels and oxidative stress, as well as boosting NOx status, in patients with T2DM.

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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)

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