Effects of Folic Acid Supplementation on Liver Enzymes, Lipid Profile, and Insulin Resistance in Patients with Non-Alcoholic Fatty Liver Disease: A Randomized Controlled Trial.

Background: Previous evidence revealed an association between folate deficiency and non-alcoholic fatty liver disease (NAFLD). This study is the first one investigating the effects of folic acid on hepatic steatosis grade, liver enzymes, insulin resistance, and lipid profile in NAFLD cases. Materials and Methods: Sixty-six participants with NAFLD were allocated randomly to take either a placebo or one oral tablet of folic acid (1 mg) on a daily basis within eight weeks. Serum folate, homocysteine, glucose, aminotransferases, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and lipids were assessed. Ultrasonography was used for assessing the liver steatosis grade. Results: The serum alanine transaminase, grade of hepatic steatosis, and aspartate transaminase significantly were decreased within both study groups; however, the between-group comparison was not statistically significant. Of note, the decrease in ALT was more pronounced in folic acid compared with the placebo group (-5.45 ± 7.45 vs. -2.19 ± 8.6 IU/L). The serum homocysteine was decreased after receiving folic acid compared to the placebo (-0.58 ± 3.41 vs. +0.4 ± 3.56 µmol/L; adjusted P = 0.054). Other outcomes did not significantly change. Conclusion: Supplementation with folic acid (1 mg/d) for eight weeks among cases with NAFLD did not change significantly the serum levels of liver enzymes, the hepatic steatosis grade, insulin resistance and lipid profile. However, it was able to prevent the increase in homocysteine in comparison with the placebo. Conducting further research is suggested with the longer duration and different doses of folic acid, adjusted to the genotypes of methylenetetrahydrofolate reductase polymorphism, among NAFLD patients.

The effects of vitamin B12 supplementation on metabolic profile of patients with non-alcoholic fatty liver disease: a randomized controlled trial.

The present study is the first effort to evaluate the effects of vitamin B12 supplementation on the serum level of liver enzymes, homocysteine, grade of hepatic steatosis, and metabolic profiles in patients with non-alcoholic fatty liver disease (NAFLD). Forty patients with NAFLD were enrolled in a double-blind placebo-controlled trial to receive either one oral tablet of vitamin B12 (1000 µg cyanocobalamin) or a placebo per day for 12 weeks. We investigated serum levels of homocysteine, aminotransferases, fasting blood glucose (FBG), lipids, malondialdehyde (MDA), and homeostasis model assessment of insulin resistance (HOMA-IR). The grade of liver steatosis and fibrosis was measured by real-time 2-dimensional shear wave elastography. Vitamin B12 supplementation significantly decreased serum levels of homocysteine compared to placebo (medians: - 2.1 vs. - 0.003 µmol/l; P = 0.038). Although serum alanine transaminase (ALT) in the vitamin B12 group decreased significantly, this change did not reach a significant level compared to the placebo group (medians: - 7.0 vs. 0.0 IU/l; P > 0.05). Despite the significant within-group decrease in FBG, MDA, and liver steatosis in the vitamin B12 group, between-group comparisons did not reveal any significant difference. Vitamin B12 supplementation might decrease serum levels of homocysteine in patients with NAFLD. The fasting blood glucose and serum levels of MDA were significantly improved in the trial group who received vitamin B12. However, these changes did not reach a significant level compared to the placebo group. In this respect, further studies with larger sample sizes, different doses, and types of vitamin B12 will reveal additional evidence.Trial Registration: At  http://irct.ir/  as IRCT20120718010333N5 on December 25, 2019.

The effects of melatonin administration on carotid intima-media thickness and pulse wave velocity in diabetic nephropathy: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Previous studies have reported that melatonin intake is inversely associated with reduced markers of atherosclerosis development such as carotid intima-media thickness (CIMT). OBJECTIVE: This study was designed to assess the effects of melatonin administration on CIMT and pulse wave velocity (PWV) in patients with diabetic nephropathy (DN). MATERIALS AND METHODS: This randomized, double-blind, placebo-controlled trial was conducted on 32 DN patients. Subjects were assigned to receive melatonin or placebo (starch) for 24 weeks. Individuals in the melatonin group (n = 19) received 10 mg/day. CIMT and PWV levels were taken at the study baseline and after 24 weeks of intervention. RESULTS: After 24 weeks of intervention, melatonin intake did not affect mean levels of left (P = 0.51) and right (P = 0.16) CIMT and maximum levels of left (P = 0.76) and right (P = 0.15) CIMT, and PWV (P = 0.55) compared with the placebo. In addition, within-group difference demonstrated a significant reduction in mean levels of right CIMT (P = 0.01) in the melatonin group. We did not observe any significant change in C-reactive protein (CRP) concentrations after melatonin intake (P = 0.81). CONCLUSIONS: Melatonin intake did not affect mean levels of left and right CIMT and maximum levels of left and right CIMT, PWV, CRP levels compared with the placebo. In addition, within-group difference demonstrated a significant reduction in mean levels of right CIMT in the melatonin group. This trial was registered at www.irct.ir as http://www.irct.ir: IRCT20200527047584N2.

The effects of selenium administration on carotid intima-media thickness and metabolic status in diabetic hemodialysis patients: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Intake of dietary antioxidants is inversely associated with reduced markers of atherosclerosis development such as carotid intima-media thickness (CIMT). OBJECTIVE: This study was designed to assess the effects of selenium supplementation on CIMT and metabolic profiles of in diabetic hemodialysis (HD) patients. MATERIALS AND METHODS: This randomized, double-blind, placebo-controlled trial was performed on 60 diabetic HD patients. Subjects were randomly assigned to receive selenium supplements or placebo (starch). Individuals in the selenium group (n = 30) received 200 µg selenium per day in the placebo group (n = 30) received for 24 weeks. Fasting blood samples were taken at the study baseline and after 24 weeks of intervention. RESULTS: Following the administration of selenium supplements, was observed a significant reduction in serum insulin levels (P = 0.003), insulin resistance (P = 0.003), total cholesterol (P = 0.008), LDL-cholesterol (P < 0.001) and C-reactive protein (CRP) (P < 0.001), and a significant increase in insulin sensitivity (P < 0.001), HDL-cholesterol (P < 0.001) and total glutathione (GSH) (P < 0.001) compared with the placebo. CONCLUSIONS: Selenium supplementation in diabetic HD patients had beneficial effects on markers of insulin metabolism, total-, LDL-, HDL-cholesterol, CRP and GSH levels. This trial was registered at www.irct.ir as http://www.irct.ir: IRCT20170513033941N47.

Effects of Carnitine Administration on Carotid Intima-media Thickness and Inflammatory Factors in Patients with Polycystic Ovary Syndrome: A Randomized, Double-blind, Placebo-controlled Trial.

BACKGROUND: This study was performed to evaluate the effects of carnitine administration on carotid intima-media thickness (CIMT) and inflammatory markers in women with polycystic ovary syndrome (PCOS). METHODS: This randomized, double-blind, placebo-controlled trial was conducted among 60 women diagnosed with PCOS according to the Rotterdam criteria, aged 18-40 years. Participants were randomly allocated into two groups to intake either 250 mg/day carnitine (n = 30) or placebo (n = 30) for 12 weeks. High-resolution carotid ultrasonography was conducted at baseline and after the 12-week intervention. RESULTS: After the 12-week intervention, compared with the placebo, carnitine supplementation resulted in a significant decrease in maximum levels of the left CIMT (-0.01 ± 0.02 vs. +0.002 mm ± 0.006 mm, P = 0.001), mean levels of the left CIMT (-0.01 ± 0.02 vs. +0.001 mm ± 0.01 mm, P = 0.001), maximum levels of the right CIMT (-0.01 ± 0.02 vs. +0.006 mm ± 0.01 mm, P < 0.001), and mean levels of the right CIMT (-0.01 ± 0.02 vs. +0.002 mm ± 0.01 mm, P = 0.001). Change in plasma nitric oxide (NO) (+2.4 ± 3.6 vs. +0.2 ± 2.3 µmol/L, P = 0.007) was significantly different between the supplemented patients and placebo group. We did not see any significant effect in serum high sensitivity C-reactive protein (hs-CRP) following the supplementation of carnitine compared with the placebo. CONCLUSIONS: Overall, carnitine administration for 12 weeks to participants with PCOS had beneficial effects on CIMT and plasma NO, but did not affect serum hs-CRP levels.

Long-term vitamin D and high-dose n-3 fatty acids' supplementation improve markers of cardiometabolic risk in type 2 diabetic patients with CHD.

This study was performed to evaluate the effects of vitamin D and n-3 fatty acids' co-supplementation on markers of cardiometabolic risk in diabetic patients with CHD. This randomised, double-blinded, placebo-controlled trial was conducted among sixty-one vitamin D-deficient diabetic patients with CHD. At baseline, the range of serum 25-hydroxyvitamin D levels in study participants was 6·3-19·9 ng/ml. Subjects were randomly assigned into two groups either taking 50 000 IU vitamin D supplements every 2 weeks plus 2× 1000 mg/d n-3 fatty acids from flaxseed oil (n 30) or placebo (n 31) for 6 months. Vitamin D and n-3 fatty acids' co-supplementation significantly reduced mean (P = 0·01) and maximum levels of left carotid intima-media thickness (CIMT) (P = 0·004), and mean (P = 0·02) and maximum levels of right CIMT (P = 0·003) compared with the placebo. In addition, co-supplementation led to a significant reduction in fasting plasma glucose (ß -0·40 mmol/l; 95 % CI -0·77, -0·03; P = 0·03), insulin (ß -1·66 µIU/ml; 95 % CI -2·43, -0·89; P < 0·001), insulin resistance (ß -0·49; 95 % CI -0·72, -0·25; P < 0·001) and LDL-cholesterol (ß -0·21 mmol/l; 95 % CI -0·41, -0·01; P = 0·04), and a significant increase in insulin sensitivity (ß +0·008; 95 % CI 0·004, 0·01; P = 0·001) and HDL-cholesterol (ß +0·09 mmol/l; 95 % CI 0·01, 0·17; P = 0·02) compared with the placebo. Additionally, high-sensitivity C-reactive protein (ß -1·56 mg/l; 95 % CI -2·65, -0·48; P = 0·005) was reduced in the supplemented group compared with the placebo group. Overall, vitamin D and n-3 fatty acids' co-supplementation had beneficial effects on markers of cardiometabolic risk.

Effects of magnesium supplementation on carotid intima-media thickness and metabolic profiles in diabetic haemodialysis patients: a randomised, double-blind, placebo-controlled trial.

This study evaluated the effects of Mg administration on carotid intima-media thickness (CIMT), glycaemic control and markers of cardio-metabolic risk in diabetic haemodialysis (HD) patients. This randomised, double-blind, placebo-controlled clinical trial was conducted in fifty-four diabetic HD patients. Participants were randomly divided into two groups to take either 250 mg/d Mg as magnesium oxide (n 27) or placebo (n 27) for 24 weeks. Mg supplementation resulted in a significant reduction in mean (P<0·001) and maximum levels of left CIMT (P=0·02) and mean levels of right CIMT (P=0·004) compared with the placebo. In addition, taking Mg supplements significantly reduced serum insulin levels (ß=-9·42 pmol/l; 95% CI -14·94, -3·90; P=0·001), homoeostasis model of assessment-insulin resistance (ß=-0·56; 95 % CI -0·89, -0·24; P=0·001) and HbA1c (ß=-0·74 %; 95 % CI -1·10, -0·39; P<0·001) and significantly increased the quantitative insulin sensitivity check index (ß=0·008; 95 % CI 0·002, 0·01; P=0·002) compared with the placebo. In addition, Mg administration led to a significant reduction in serum total cholesterol (ß=-0·30 mmol/l; 95% CI -0·56, -0·04; P=0·02), LDL-cholesterol (ß=-0·29 mmol/l; 95% CI -0·52, -0·05; P=0·01), high-sensitivity C-reactive protein (hs-CRP) (P<0·001) and plasma malondialdehyde (MDA) (P=0·04) and a significant rise in plasma total antioxidant capacity (TAC) levels (P<0·001) compared with the placebo. Overall, we found that taking Mg for 24 weeks by diabetic HD patients significantly improved mean and maximum levels of left and mean levels of right CIMT, insulin metabolism, HbA1c, total cholesterol and LDL-cholesterol, hs-CRP, TAC and MDA levels.

The Effects of Omega-3 and Vitamin E Co-supplementation on Carotid Intima-media Thickness and Inflammatory Factors in Patients with Polycystic Ovary Syndrome.

OBJECTIVES: We sought to evaluate the effects of omega-3 and vitamin E co-supplementation on carotid intima-media thickness (CIMT) and inflammatory factors in patients with polycystic ovary syndrome (PCOS). METHODS: This randomized, double-blind, placebo-controlled trial was done among 60 women with PCOS. Participants were randomly assigned into two groups (n = 30 each group) and assigned to take either 1000 mg omega-3 plus 400 IU vitamin E supplements or a placebo for 12 weeks. RESULTS: Compared with placebo, omega-3 and vitamin E co-supplementation led to significant decreases in maximum levels of left CIMT (-0.006±0.006 vs. +0.002±0.007 mm, p < 0.001), mean levels of left CIMT (-0.005±0.006 vs. +0.002±0.010 mm, p = 0.010), maximum levels of right CIMT (-0.006±0.010 vs. +0.006±0.010 mm, p = 0.010), and mean levels of right CIMT (-0.005±0.005 vs. +0.001±0.010 mm, p = 0.020). Change in high-sensitivity C-reactive protein (hs-CRP) (-390.6±942.9 vs. +237.0±754.3 ng/mL, p = 0.006) was significantly different between the supplemented patients and placebo group. We did not observe any significant effect in plasma nitric oxide (NO) values following supplementation with omega-3 plus vitamin E compared with the placebo. CONCLUSIONS: Co-supplementation with omega-3 and vitamin E for 12 weeks among patients with PCOS had beneficial effects on CIMT and serum hs-CRP values, but unchanged NO values.

The Effects of Vitamin D Supplementation on Biomarkers of Inflammation and Oxidative Stress in Diabetic Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

In this systematic review and meta-analysis of randomized controlled trials (RCTs), the effects of vitamin D supplementation on biomarkers of inflammation and oxidative stress in diabetic patients are summarized. The following databases were searched up to December 2017: MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. The quality of the relevant extracted data was assessed according to the Cochrane risk of bias tool. Data were pooled using the inverse variance method and expressed as mean difference with 95% Confidence Intervals (95% CI). Heterogeneity between studies was assessed by the Cochran Q statistic and I-squared tests (I2). Overall, 33 studies were included in the meta-analyses. Vitamin D supplementation were found to significantly reduce serum high-sensitivity C-reactive protein (hs-CRP) (WMD 0.27; 95% CI, - 0.35, - 0.20; p<0.001) and malondialdehyde (MDA) levels (WMD - 0.43, 95% CI - 0.62, - 0.25, p<0.001) in diabetic patients. In addition, vitamin D supplementation were found to increase markers of nitric oxide (NO) release (WMD 4.33, 95% CI 0.96, 7.70), total serum antioxidant capacity (TAC) (WMD 57.34, 95% CI 33.48, 81.20, p<0.001) and total glutathione (GSH) levels (WMD 82.59, 95% CI 44.37, 120.81, p<0.001). Overall, this meta-analysis shows that in diabetic patients, taking vitamin D had significant effects on hs-CRP and MDA levels, and significantly increased NO, TAC and GSH levels.

Long-Term Vitamin D Supplementation Affects Metabolic Status in Vitamin D-Deficient Type 2 Diabetic Patients with Coronary Artery Disease.

Background: Vitamin D might be beneficial in diabetic patients with coronary artery disease (CAD) through its favorable effects on metabolic profiles and biomarkers of inflammation and oxidative stress.Objective: This study was performed to examine the effects of 6 mo of vitamin D supplementation on metabolic status in diabetic patients with CAD.Methods: This randomized, double-blind, placebo-controlled clinical trial was conducted in 60 vitamin D-deficient diabetic patients with CAD aged 40-85 y. Subjects were randomly assigned into 2 groups to take either 50,000-IU vitamin D supplements (n = 30) or placebo (n = 30) every 2 wk for 6 mo. Fasting blood samples were obtained at the beginning of the study and after the 6-mo intervention to quantify glycemic indicators, lipid concentrations, and biomarkers of inflammation and oxidative stress.Results: Compared with placebo, vitamin D supplementation resulted in significant reductions in fasting plasma glucose (-14.9 ± 7.1 compared with +19.3 ± 7.1 mg/dL; P = 0.001), serum insulin (-2.7 ± 1.1 compared with +1.8 ± 1.1 µIU/mL; P = 0.006), homeostasis model assessment of insulin resistance (-0.7 ± 0.3 compared with +0.5 ± 0.3; P = 0.01), and ß cell function (-9.1 ± 4.2 compared with +5.7 ± 4.2; P = 0.01) and a significant increase in serum vitamin D (+6.8 ± 0.9 compared with +0.1 ± 0.9 ng/mL; P < 0.001) and the Quantitative Insulin Sensitivity Check Index (+0.008 ± 0.004 compared with -0.007 ± 0.004; P = 0.01). In addition, changes in serum high-sensitivity C-reactive protein (hs-CRP; -1.0 ± 0.5 compared with +0.6 ± 0.5 µg/mL; P = 0.02), plasma nitric oxide (NO; +7.0 ± 2.0 compared with -4.6 ± 2.0 µmol/L; P < 0.001), total reduced glutathione (GSH; +104 ± 16.4 compared with +24.8 ± 16.4 µmol/L; P = 0.001), and malondialdehyde concentrations (-0.2 ± 0.1 compared with +0.2 ± 0.1 µmol/L; P < 0.001) in the supplemented group were significantly different from the changes in these indicators in the placebo group.Conclusions: Overall, 6 mo of vitamin D supplementation among vitamin D-deficient diabetic patients with CAD had beneficial effects on glycemic control and serum hs-CRP, NO, GSH, and malondialdehyde concentrations. This trial was registered on the Iranian website (www.irct.ir) for registration of clinical trials as IRCT201510315623N56.

The Effects of Folate Supplementation on Carotid Intima-Media Thickness and Metabolic Status in Patients with Metabolic Syndrome.

BACKGROUND: This study was carried out to evaluate the effects of folate supplementation on carotid intima-media thickness (CIMT) and metabolic status among patients with metabolic syndrome (MetS). METHODS: This randomized, double-blind, placebo-controlled trial was conducted among 60 patients with type 2 diabetes mellitus and coronary heart disease. They were all overweight in the age range 40-85 years. Participants were randomly divided into 2 groups: group A (n = 30) received 5 mg folate supplements and group B (n = 30) received placebo for 12 weeks. RESULTS: Folate supplementation resulted in a significant reduction in maximum levels of left CIMT (-0.05 ± 0.13 vs. +0.02 ± 0.11 mm, p = 0.01) compared with the placebo. Changes in fasting plasma glucose (-2.2 ± 37.5 vs. +30.2 ± 65.8 mg/dl, p = 0.02), serum insulin concentration (-2.0 ± 10.7 vs. +3.0 ± 7.6 µIU/ml, p = 0.04) and homeostasis of assessment-estimated insulin resistance (-0.6 ± 2.3 vs. +0.9 ± 2.3, p = 0.01) in supplemented patients were significantly different from those of patients in the placebo group. Changes in serum triglycerides (p = 0.04), high-density lipoprotein-cholesterol (p = 0.001), high sensitivity C-reactive protein (p = 0.01) and plasma nitric oxide concentrations (p < 0.001) were significantly different between the supplemented patients and placebo group. CONCLUSIONS: Overall, 5 mg/day folate supplementation for 12 weeks among patients with MetS had beneficial effects on CIMT and the metabolic status.

The effects of vitamin D, K and calcium co-supplementation on carotid intima-media thickness and metabolic status in overweight type 2 diabetic patients with CHD.

This study was conducted to examine the effects of vitamin D, K and Ca co-supplementation on carotid intima-media thickness (CIMT) and metabolic status in overweight diabetic patients with CHD. This randomised, double-blind, placebo-controlled trial was conducted among sixty-six diabetic patients with CHD. Participants were randomly allocated into two groups to take either 5µg vitamin D, 90 µg vitamin K plus 500 mg Ca supplements (n 33) or placebo (n 33) twice a day for 12 weeks. Fasting blood samples were obtained at the beginning of the study and after the 12-week intervention period to determine related markers. Vitamin D, K and Ca co-supplementation resulted in a significant reduction in maximum levels of left CIMT (-0·04 (sd 0·22) v. +0·04 (sd 0·09) mm, P=0·02). Changes in serum vitamin D (+6·5 (sd 7·8) v. +0·4 (sd 2·2) ng/ml, P<0·001), Ca (+0·6 (sd 0·3) v. +0·1 (sd 0·1) mg/dl, P<0·001) and insulin concentrations (-0·9 (sd 3·1) v. +2·6 (sd 7·2) µIU/ml, P=0·01), homoeostasis model for assessment of estimated insulin resistance (-0·4 (sd 1·2) v. +0·7 (sd 2·3), P=0·01), ß-cell function (-2·1 (sd 9·0) v. +8·9 (sd 23·7), P=0·01) and quantitative insulin sensitivity check index (+0·007 (sd 0·01) v. -0·006 (sd 0·02), P=0·01) in supplemented patients were significantly different from those in patients in the placebo group. Supplementation resulted in significant changes in HDL-cholesterol (+2·7 (sd 7·0) v. -2·5 (sd 5·7) mg/dl, P=0·002), high-sensitivity C-reactive protein (-1320·1 (sd 3758·3) v. +464·0 (sd 3053·3) ng/ml, P=0·03) and plasma malondialdehyde concentrations (-0·4 (sd 0·5) v. -1·0 (sd 1·1) µmol/l, P=0·007) compared with placebo. Overall, vitamin D, K and Ca co-supplementation for 12 weeks among diabetic patients with CHD had beneficial effects on maximum levels of left CIMT and metabolic status. The effect of vitamin D, K and Ca co-supplementation on maximum levels of left CIMT could be a chance finding.