Effect of oral vitamin E (alpha-tocopherol) supplementation on vascular endothelial function in Type 2 diabetes mellitus. Oral L-arginine and vitamins E and C improve endothelial function in women with type 2 diabetes Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels. Uric Acid Restores Endothelial Function in Patients With Type 1 Diabetes and Regular Smokers A randomised controlled trial evaluating the impact of targeted vitamin D supplementation on endothelial function in type 2 diabetes mellitus: The DIMENSION trial Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus. Randomized controlled trial of vitamin D supplement on endothelial function in patients with type 2 diabetes. Supplementation with vitamins C and E improves arterial stiffness and endothelial function in essential hypertensive patients. The Diabetes and Pre-eclampsia Intervention Trial. Food selection based on high total antioxidant capacity improves endothelial function in a low cardiovascular risk population. Vitamin D 20,000 IU per Week for Five Years Does Not Prevent Progression From Prediabetes to Diabetes. Endothelial function, insulin action and cardiovascular risk factors in young healthy adult offspring of parents with Type 2 diabetes: effect of vitamin E in a randomized double-blind, controlled clinical trial. Six months of resveratrol supplementation has no measurable effect in type 2 diabetic patients. A randomized, double blind, placebo-controlled trial. Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: role of fat and carbohydrate meals. Impact of Vitamin E Supplementation on Blood Pressure and Hs-CRP in Type 2 Diabetic Patients | doi: 10.5681/hpp.2012.009. A systematic review protocol examining the effect of vitamin D supplementation on endothelial function Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes. Measurement feasability of advanced glycated end-products from skin samples after antioxidant vitamin supplementation in patients with type 2 diabetes. Smoking-Induced Monocyte Dysfunction Is Reversed by Vitamin C Supplementation In Vivo Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. Effects of vitamins C and E on oxidative stress markers and endothelial function in patients with systemic lupus erythematosus: a double blind, placebo controlled pilot study. Effect of paricalcitol on endothelial function and inflammation in type 2 diabetes and chronic kidney disease. Antioxidant Vitamins C and E Improve Endothelial Function in Children With Hyperlipidemia: Endothelial Assessment of Risk from Lipids in Youth (EARLY) Trial
AIMS Vascular endothelial dysfunction , an early marker of atherosclerosis , has been demonstrated in Type 2 diabetes mellitus ( DM ) .  Vitamin E preserves endothelial function in animal models of diabetes and reduces cardiovascular risk . We examined endothelial function and the effect of vitamin E supplements in uncomplicated Type 2 DM . METHODS Forty-eight subjects with Type 2 DM and 21 controls had endothelial function assessed using forearm venous occlusion plethysmography with endothelium-independent ( sodium nitroprusside ) and dependent ( acetylcholine , bradykinin ) vasodilators . Those with diabetes received 1600 i.u . daily oral alpha-tocopherol or placebo , double-blind for 8 weeks , and had endothelial function reassessed . RESULTS The diabetic group had higher HbA1c ( 6.9+/-1.4 vs 4.8+/-0.6 % ; P<0.01 ) and systolic ( 145+/-15 vs. 130+/-16 mm Hg ; P<0.01 ) but not diastolic blood pressure ( 79+/-8 vs. 76+/-9 mm Hg ; P = 0.15 ) . There was blunted vasodilation to acetylcholine ( 15 microg/min ; P<0.01 ) in subjects with diabetes . Vasodilation to sodium nitroprusside and bradykinin was similar ( all P>0.1 ) . Alpha-tocopherol did not affect vasodilation to nitroprusside ( P>0.1 ) , acetylcholine ( P>0.1 ) or bradykinin ( P>0.1 ) . CONCLUSIONS There may be receptor-specific endothelial dysfunction in subjects with uncomplicated Type 2 DM . This is not improved by treatment with alpha-tocopherol Endothelial dilator function is impaired in people with type 2 diabetes mellitus ( T2DM ) . Prior research indicates that this can be improved with intravenous administration of ascorbate or L-arginine , but whether these agents have this effect when administered by the clinical ly practical oral route is unknown . To investigate this question , 10 premenopausal women with T2DM and 10 healthy , premenopausal , non-diabetic women received , in r and om sequence , a 1-week administration of oral L-arginine ( 9 g daily ) or vitamins E ( 1800 mg ) and C ( 1000 mg ) with an intervening 1-week washout period . Flow-mediated brachial artery dilation ( FMD ) was measured by ultrasonography and forearm blood flow was measured by plethysmography before and following blood pressure cuff-induced forearm ischemia before and after each week of treatment . At baseline , the women with T2DM had lesser FMD responses ( 0.028 ± 0.006 cm vs 0.056 ± 0.008 cm , p , 0.05 ) . Post-ischemic forearm hyperemia was reduced at baseline in T2DM compared with controls ( 16.4 ± 1.8 vs 26.0 ± 1.4 ml 100 ml- 1 min- 1 , p < 0.05 ) . Administration of L-arginine caused a 50 ± 12 % increase in FMD in T2DM ( p < 0.05 ) and raised post-ischemic forearm blood flow by 29 ± 8 % ( p < 0.05 ) . No significant changes were seen in controls . Administration of vitamins E and C in women with T2DM produced an increase in the brachial artery diameter response of 79 ± 15 % ( p < 0.05 ) , but did not significantly increase the hyperemic blood flow response ( p = NS ) . No significant changes in the responses of controls from pre to post vitamin administration were observed . We concluded that administration of two types of oral agents improved measures of endothelial function in people with T2DM AIMS To test whether a single large dose of vitamin D2 can improve endothelial function in patients with Type 2 diabetes mellitus and low serum 25-hydroxyvitamin D levels . METHODS Double-blind , parallel group , placebo-controlled r and omized trial . A single dose of 100,000 IU vitamin D2 or placebo was administered to patients with Type 2 diabetes over the winter , when levels of circulating 25-hydroxyvitamin D were likely to be lowest . Patients were enrolled if their baseline 25-hydroxyvitamin D level was < 50 nmol/l .  Endothelial function and blood pressure were measured and fasting blood sample s were taken at baseline and 8 weeks after administration of vitamin D. RESULTS Forty-nine per cent of subjects screened had 25-hydroxyvitamin D levels < 50 nmol/l . Thirty-four subjects completed the study , with a mean age of 64 years and a baseline 25-hydroxyvitamin D level of 38.3 nmol/l .  Vitamin D supplementation  increased 25-hydroxyvitamin D levels by 15.3 nmol/l relative to placebo and significantly improved flow mediated vasodilatation ( FMD ) of the brachial artery by 2.3 % . The improvement in FMD remained significant after adjusting for changes in blood pressure .  Vitamin D supplementation significantly decreased systolic blood pressure by 14 mmHg compared with placebo ; this did not correlate with change in FMD . CONCLUSIONS Vitamin D insufficiency is common in patients with Type 2 diabetes during winter in Scotl and . A single large dose of oral vitamin D2 improves endothelial function in patients with Type 2 diabetes and vitamin D insufficiency Endothelial dysfunction is a characteristic finding in both patients with type 1 diabetes and in regular smokers and is an important precursor to atherosclerosis . The urate molecule has antioxidant properties , which could influence endothelial function . The impact of acutely raising uric acid concentrations on endothelial function was studied in eight men with type 1 diabetes , eight healthy regular smokers , and eight age-matched healthy control subjects in a r and omized , four-way , double-blind , placebo-controlled study . Subjects received 1,000 mg uric acid i.v . in vehicle , 1,000 mg vitamin C as a control antioxidant , vehicle alone , or 0.9 % saline on separate occasions over 1 h. Forearm blood flow responses to intrabrachial acetylcholine and sodium nitroprusside were assessed using venous occlusion plethysmography . Responses to  acetylcholine  , but not sodium nitroprusside , were impaired in patients with diabetes ( P < 0.001 ) and in smokers ( P < 0.005 ) compared with control subjects . Administration of uric acid and vitamin C selectively improved acetylcholine responses in patients with type 1 diabetes ( P < 0.01 ) and in regular smokers ( P < 0.05 ) . Uric acid administration improved endothelial function in the forearm vascular bed of patients with type 1 diabetes and smokers , suggesting that high uric acid concentrations in vivo might serve a protective role in these and other conditions associated with increased cardiovascular risk We sought to determine if vitamin D supplementation , to target 25(OH)D concentrations of 30–40 ng/mL , improves endothelial function in Singapore ’s multi-ethnic type 2 diabetes mellitus population . We r and omised 64 type 2 diabetes mellitus patients with hypovitaminosis D to cholecalciferol 4000 International Unit/matching placebo [ baseline 25(OH)D < 20 ng/mL ] or cholecalciferol 2000 International Unit/matching placebo [ baseline 25(OH)D : 20–30 ng/mL ] daily for 16 weeks with a down titration at 8 weeks if 25(OH)D > 30 ng/mL. Endothelial function was assessed by peripheral tonometry ( reactive hyperaemia index – endothelial peripheral arterial tonometry ) and vascular biomarkers : E-selectin , von-Willebr and factor and high-sensitivity C-reactive protein . We compared the change from baseline parameters in the two groups using Student ’s t-test or Kruskal – Wallis test . A log-normal multivariate regression analysis was used to adjust for relevant baseline variables . The median reactive hyperaemia index in the vitamin D group increased from 0.65 ( interquartile range : 0.42 ) to 0.73 ( interquartile range : 0.36 ) , whereas it decreased from 0.73 ( interquartile range : 0.65 ) to 0.65 ( interquartile range : 0.38 ) ( p = 0.02 ) in the placebo group . After adjustment for baseline variables , the change was not statistically significant for reactive hyperaemia index ( p = 0.07 ) and for other vascular biomarkers ( p > 0.05 ) . Targeted vitamin D supplementation for 16 weeks result ed in a small but non-significant improvement in endothelial function in a type 2 diabetes mellitus cohort Oxidative stress decreases the bioavailability of endothelium-derived nitric oxide in diabetic patients . We investigated whether impaired endothelium-dependent vasodilation ( EDV ) in diabetes can be improved by long-term administration of oral antioxidants .  Forty-nine diabetic subjects [ 26 Type 1 ( T1 ) and 23 Type 2 ( T2 ) ] and 45 matched healthy control subjects were r and omized to receive oral vitamin C ( 1,000 mg ) and vitamin E ( 800 IU ) daily or matching placebo for 6 mo . Vascular ultrasonography was used to determine brachial artery EDV and endothelium-independent vasodilation ( EIV ) . EDV was decreased in both T1 ( 4.9 + /- 0.9 % , P = 0.015 ) and T2 ( 4.1 + /- 1.0 % , P < 0.01 ) subjects compared with control subjects ( 7.7 + /- 0.7 % ) . EIV was decreased in T2 ( 15.0 + /- 1.2 % , P < 0.01 ) but not T1 subjects ( 18.5 + /- 2.3 % , P = 0.3 ) compared with controls ( 21.8 + /- 1.8 % ) . Administration of antioxidant vitamins increased EDV in T1 ( by 3.4 + /- 1.4 % , P = 0.023 ) but not T2 subjects ( by 0.5 . + /- 0.4 % , P = 0.3 ) . Antioxidant therapy had no significant affect on EIV .  Oral antioxidant therapy improves EDV in T1 but not T2 diabetes . These results are consistent with the lack of clinical benefit in studies that have included primarily T2 diabetic patients BACKGROUND Suboptimal vitamin D status is associated with endothelial dysfunction and an increased risk of cardiovascular diseases but it is unclear whether vitamin D supplementation is beneficial . The aim was to investigate the effect of vitamin D supplementation on endothelial function in patients with type 2 diabetes mellitus ( DM ) . METHODS In a double-blind , placebo-controlled trial , we r and omized 100 type 2 DM patients to vitamin D supplement  ( 5000 IU/day , n = 50 ) or placebo ( controls , n = 50 ) for 12 weeks . Assessment of vascular function with brachial artery flow-mediated dilatation ( FMD ) , circulating levels of endothelial progenitor cells ( EPCs ) and brachial-ankle pulse wave velocity , and metabolic parameter , high-sensitivity C-reactive protein ( hsCRP ) and oxidative stress markers were performed before and after the supplementation . RESULTS After 12 weeks , vitamin D treated patients had significant increases in serum 25-hydroxyvitamin D [ 25(OH)D ] concentration ( treatment effect 34.7 ng/mL , 95 % CI 26.4 - 42.9 , P < 0.001 ) and serum ionized calcium ( treatment effect 0.037 mmol/L , 95 % CI 0.007 - 0.067 , P = 0.018 ) ; decreased serum parathyroid hormone concentration ( treatment effect -0.55 pmol/L , 95 % CI -1.08 to -0.02 , P = 0.042 ) compared to patients who received placebo . Nevertheless , vitamin D supplementation did not improve vascular function as determined by FMD , circulating EPC count or baPWV ( all P > 0.05 ) . Furthermore , hsCRP , oxidative stress markers , low- and high-density lipoprotein and glycated hemoglobin were also similar between two groups ( all P > 0.05 ) . CONCLUSION In patients with type 2 DM , 12 weeks oral supplementation of vitamin D did not significantly affect vascular function or serum biomarkers of inflammation and oxidative stress . CLINICAL TRIAL NUMBER HKCTR-867 , www.hk clinical trials.com BACKGROUND Essential hypertension is characterized by endothelial dysfunction , arterial stiffness , and increased oxidative stress . We evaluated the effect of short-term combined treatment with the antioxidants vitamins C and E on endothelial function , arterial stiffness , and oxidative stress in untreated essential hypertensive patients . METHODS A r and omized , double-blind , placebo-controlled , crossover study design was used to assign 30 male essential hypertensive patients to either vitamin C ( 1 g ) and vitamin E ( 400 IU ) or placebo for 8 weeks . Endothelium-dependent response was assessed as flow-mediated dilation ( FMD ) of the brachial artery . Arterial stiffness was assessed as central pulse wave velocity ( PWV ) and augmentation index ( AIx ) . Plasma markers of oxidative stress and antioxidant status were measured . RESULTS After vitamin supplementation , FMD was significantly improved . Central PWV was significantly reduced , while AIx tended to decrease . Plasma vitamin levels and antioxidant capacity increased significantly . Levels of oxidative stress decreased . Changes in central PWV were related to changes in levels of oxidative stress . CONCLUSIONS Combined treatment with vitamins C and E has beneficial effects on endothelium-dependent vasodilation and arterial stiffness in untreated , essential hypertensive patients . This effect is associated with changes in plasma markers of oxidative stress OBJECTIVE Rates of  pre-eclampsia  in women with type 1 diabetes are two to four times higher than in normal pregnancies . Diabetes is associated with antioxidant depletion and increased free radical production , and an increasing body of evidence suggests that oxidative stress and endothelial cell activation may be relevant to disease pathogenesis in pre-eclampsia . The Diabetes and Pre-eclampsia Intervention Trial ( DAPIT ) aims to establish if pregnant women with type 1 diabetes supplemented with vitamins C and E have lower rates of pre-eclampsia and endothelial activation compared with placebo treatment . METHODS DAPIT is a r and omised multicentre double-blind placebo-controlled trial that will recruit 756 pregnant women with type 1 diabetes from 20 metabolic-antenatal clinics in the UK over 4 years . Women are r and omised to daily vitamin C ( 1000 mg ) and vitamin E ( 400 IU ) or placebo at 8 - 22 weeks of gestation until delivery . Maternal venous blood is obtained at r and omisation , 26 and 34 weeks , for markers of endothelial activation and oxidative stress and to assess glycaemic control . The primary outcome of DAPIT is pre-eclampsia . Secondary outcomes include endothelial activation ( PAI-1/PAI-2 ) and birthweight centile BACKGROUND AND AIMS Oxidative stress has been advocated as a major cause for cardiovascular disease ( CVD ) , and low plasma antioxidant concentrations are associated with endothelial dysfunction , the first step towards atherosclerosis . However , although the antioxidant content in fruits and vegetables may explain at least in part their protective effect against CVD , supplementation with antioxidant vitamins fails to improve endothelial function and reduce CVD risk . The aim of this study was to investigate the impact of a diet rich in antioxidants on endothelial function measured by flow-mediated dilatation ( FMD ) in volunteers at low cardiovascular risk . METHODS AND RESULTS In a crossover trial , 24 subjects ( 13 women , mean age 61 ± 3 years ) , received , in a r and omised order , a 14-day high ( HT ) and a 14-day low ( LT ) antioxidant diets , with a 2-week wash-out ( WO ) in between . Both diets were comparable in daily portions of fruits and vegetables , and in alcohol , fibre and macronutrient intake , but differed in their total antioxidant capacity . Before and after each diet , anthropometrics , blood pressure , fasting plasma glucose , lipid profile , hepatic enzymes , circulating antioxidant concentrations , high sensitivity C-reactive protein ( hs-CRP ) and FMD were assessed . FMD increased significantly during the HT diet compared to the LT ( p < 0.000 ) . FMD values were 2.3 % higher after HT compared with LT ( p < 0.001 ) after adjustment for age , gender and diet order . α-tocopherol increased significantly ( p < 0.05 ) and hs-CRP and of γ-glutamyltranspeptidase decreased significantly ( p < 0.05 and p < 0.01 , respectively ) during the HT diet , compared with the LT diet . CONCLUSIONS A short-term HT diet improves endothelial function in volunteers at low cardiovascular risk , which may further reduce their risk of CVD CONTEXT Vitamin D deficiency is associated with insulin resistance and risk of future diabetes . OBJECTIVE The objective of the study was to test whether supplementation with vitamin D to subjects with prediabetes will prevent progression to type 2 diabetes mellitus ( T2DM ) . DESIGN This was a r and omized controlled trial performed in 2008 through 2015 . SETTING The study was conducted at the clinical research unit at a teaching hospital . PATIENTS Five hundred eleven subjects ( mean age 62 y , 314 males ) with prediabetes diagnosed with an oral glucose tolerance test as part of the Tromsø Study 2007–2008 were included . A total of 256 were r and omized to vitamin D and 255 to placebo .  Twenty-nine subjects in the vitamin D and 24 in the placebo group withdrew because of adverse events . INTERVENTIONS Interventions included vitamin D ( cholecalciferol ) 20 000 IU/wk vs placebo for 5 years . Annual oral glucose tolerance tests were performed . MAIN OUTCOME MEASURE Progression to T2DM was the main outcome measure . Secondary outcomes were change in glucose levels , insulin resistance , serum lipids , and blood pressure . RESULTS The mean baseline serum 25-hydroxyvitamin D level was 60 nmol/L ( 24 ng/mL ) . One hundred three in the vitamin D and 112 in the placebo group developed T2DM ( hazard risk 0.90 ; 95 % confidence interval 0.69–1.18 , Cox regression , P = .45 , intention to treat analysis ) . No consistent significant effects on the other outcomes were seen . Subgroup analyses in subjects with low baseline 25-hydroxyvitamin D yielded similar results . No serious side effects related to the intervention were recorded . CONCLUSIONS In subjects without vitamin D deficiency , vitamin D supplementation is unlikely to prevent progression from prediabetes to diabetes . Very large studies with inclusion of vitamin D-deficient subjects will probably be needed to show such a putative effect . This study tested if supplementation with  vitamin D to subjects with prediabetes will prevent progression to type 2 diabetes ( T2DM ) BACKGROUND AND AIMS Endothelial dysfunction , insulin resistance and oxidative stress are believed to be central and associated mechanisms in atherogenesis . We aim ed to determine the effect of the antioxidant vitamin E on endothelial function , insulin action and cardiovascular risk markers in young healthy adult offspring of parents with Type 2 diabetes . METHODS Healthy , glucose-tolerant adults ( 18 - 38 years ) , 14 ( 12 male/2 female ) with at least one parent with Type 2 diabetes , and 14 ( 12 male/2 female ) subjects with no family history of diabetes ( controls ) were studied . Insulin action was assessed by euglycaemic hyperinsulinaemic clamp ( 1 mU/kg/min ) . Endothelial function was assessed by forearm blood flow ( FBF ) responses to intra-brachial artery infusions of acetylcholine ( ACh ) ( endothelium-dependent vasodilation ) , sodium nitroprusside ( SNP ) ( endothelium-independent vasodilation ) and N(G)-monomethyl L-arginine ( LNMMA ) ( nitric oxide synthase inhibition ) . Thirteen offspring ( 18 - 38 years , 11 male/2 female , BMI < 30 kg/m2 ) completed a r and omized , double-blind , crossover trial ( 12 weeks vitamin E 800 IU/day or placebo , 6-week washout ) . RESULTS Exogenous glucose infusion rates to maintain euglycaemia were positively associated with response to acetylcholine in offspring ( r = 0.61 , P < 0.05 ) , and were linked with triglycerides .  Vitamin E had no effect on endothelial function , insulin action or cardiovascular risk markers in healthy adult offspring of parents with Type 2 diabetes . CONCLUSIONS Our results support a positive association between insulin action and endothelial-dependent vasodilation in young healthy adult offspring of parents with Type 2 diabetes , but indicate no effect of vitamin E on these parameters The polyphenol resveratrol is considered to exert many beneficial actions , such as antioxidant , anti-inflammatory , insulin-sensitizer and anticancer effects . Its benefits in patients with type 2 diabetes mellitus ( T2DM ) are controversial . Our aims were to determine whether resveratrol supplementation at two different dosages ( 500 and 40mg/day ) for 6 months i ) reduced the concentrations of C-reactive-protein ( CRP ) and ii ) ameliorated the metabolic pattern of T2DM patients .  In the present double-blind , r and omized , placebo-controlled trial , 192 T2DM patients were r and omized to receive resveratrol 500mg/day ( Resv500arm ) , resveratrol 40mg/day ( Resv40arm ) or placebo for 6-months . At baseline and at the trial end , CRP values , anthropometric , metabolic and liver parameters were determined . No serious adverse event occurred . A dose-dependent , though not significant , CRP decrease of 5.6 % ( Resv40arm ) and 15.9 % ( Resv500arm ) was observed vs placebo . We failed to detect significant differences in weight , BMI , waist circumference , and values of arterial blood pressure , fasting glucose , glycated hemoglobin , insulin , C-peptide , free fatty acids , liver transaminases , uric acid , adiponectin , interleukin-6 , in both the Resv500 and Resv40 arms vs placebo . Total cholesterol and triglycerides slightly increased in the Resv500arm . Subgroup analyses revealed that lower diabetes duration ( in both Resv500 and Resv40arms ) , and , in the Resv500arm , younger age , aspirin use and being a smoker were associated with a significantly higher CRP reduction vs placebo . The supplementations with 40mg/day or 500mg/day resveratrol did neither reduce CRP concentrations , nor improve the metabolic pattern of T2DM patients OBJECTIVES To compare the effect of a high-fat meal and a high-carbohydrate meal ( pizza ) , with and without antioxidant vitamins , on endothelial activation in healthy subjects and in patients with type 2 diabetes mellitus . BACKGROUND The postpr and ial state is becoming increasingly acknowledged to affect some early events of atherogenesis . METHODS In a r and omized , observer-blinded , crossover study , 20 newly diagnosed type 2 diabetic patients and 20 age- and gender-matched healthy subjects received two meals at one-week intervals : a high-fat meal ( 760 calories ) and an isoenergetic high-carbohydrate meal ( non-cheese pizza ) . In all subjects , the same meals were repeated immediately following ingestion of vitamin E , 800 IU , and ascorbic acid , 1,000 mg . RESULTS In normal subjects , the high-fat meal increased the plasma levels of tumor necrosis factor-alpha ( TNF-alpha ) , interleukin-6 ( IL-6 ) , intercellular adhesion molecule-1 ( ICAM-1 ) and vascular cell adhesion molecule-1 ( VCAM-1 ) , which were prevented by vitamins . No change in these parameters occurred after pizza ingestion or pizza ingestion with vitamins . In diabetic patients , basal concentrations of glucose , cytokines and adhesion molecules were significantly higher than in nondiabetic controls . Both meals significantly increased cytokine and adhesion molecule levels , but the increase was more sustained following the high-fat meal . There was no significant change from baseline when vitamin supplementation accompanied each meal . There was a relationship between changes in serum triglycerides and changes in TNF-alpha ( r = 0.39 , p < 0.01 ) , IL-6 ( r = 0.28 , p < 0.05 ) and VCAM-1 ( r = 0.25 , p < 0.05 ) , and between changes in plasma glucose and changes in IL-6 ( r = 0.36 , p < 0.01 ) and ICAM-1 ( r = 0.31 , p < 0.02 ) . CONCLUSIONS An oxidative mechanism mediates endothelial activation induced by post-meal hyperlipidemia and hyperglycemia BACKGROUND Type 2 diabetes mellitus ( T2DM ) is a major public health problem worldwide . Hypertension and inflammation are well recognized as risk factors for the macrovascular complications of diabetes . The aim of this study was to assess the impact of vitamin E supplementation on blood pressure ( BP ) , serum high-sensitivity C-reactive protein ( hs-CRP ) and fasting blood glucose in patients with T2DM . METHODS In a double blind , r and omized , controlled clinical trial , 83 patients with T2DM were divided r and omly into two groups of vitamin E ( 400 mg/d , n=42 ) and placebo ( n=41 ) . All patients received the pearls for 8 weeks . Baseline and eighth week BP , serum hs-CRP , fasting blood glucose , anthropometric and dietary intake data were obtained from each patient . Data were analyzed using SPSS version 11.5 . RESULTS Vitamin E supplementation significantly increased serum levels of vitamin E  ( P < 0.001 ) and decreased mean arterial pressure and fasting blood glucose ( P = 0.047 , P = 0.028 , respectively ) in vitamin E group as compared with placebo group . A significant decrease in systolic blood pressure and diastolic blood pressure was observed in the vitamin E group comparing with baseline values ( all P < 0.01 ) . There were no significant changes in serum hs-CRP in both of the studied groups . CONCLUSION Vitamin E had beneficial effects on serum vitamin E , BP and blood glucose in patients with T2DM . Improvement in BP and glucose control may contribute to reducing complications of diabetes including cardiovascular risk in these patients Introduction Vitamin D has potential benefits for extraskeletal health . These could include an anti-inflammatory effect as well as a reduction in endothelial dysfunction . We aim to provide quality evidence for the hypothesis that supplementation with vitamin D will improve endothelial function ( EF ) , possibly through the abrogation of systemic inflammation . Methods and analysis We will conduct a systematic review of all r and omised controlled trials on  vitamin D supplementation and EF lasting 12 weeks or more . The search will cover the period 2000–2015 and include studies that describe direct measures of EF  , markers of endothelial cell ( EC ) activation  and if concurrently reported , indicators of systemic inflammation  . Study selection will follow the Preferred Reporting Items for Systematic Review s and Meta-Analyses ( PRISMA ) guidelines and study quality will be assessed by the Jadad score in addition to an evaluation of allocation concealment and data analysis . If sufficient data are available , a meta- analysis will be conducted . The effect sizes will be generated using Hedges ’ g score , for both fixed and r and om effect models . I2 statistics and Galbraith plots will be used to assess heterogeneity and identify their potential sources . Potential publication and small sample size bias will be assessed by visual inspections of funnel plots and also Egger 's test . Meta-regression analysis ( if feasible ) will be conducted with restricted maximum likelihood ( REML ) estimation method , controlling for potential confounders ( demographics , study methods , location , etc ) . A backward elimination process will be applied in the regression modelling procedure . Subgroup analysis , conditional on number of studies retrieved and their sample size , will be stratified on participant disease category , total dose administered , degree of 25(OH)D change and type of supplement used . Ethics and dissemination Formal ethical approval is not required as primary data will not be collected . The results will be disseminated through a peer- review ed publication , conference presentation and the popular press . Trial registration number International Prospect i ve Register for Systematic Review s ( PROSPERO ) number CRD42014013523 Diets rich in green , leafy vegetables have been shown to lower blood pressure ( BP ) and reduce the risk of cardiovascular disease .  Green , leafy vegetables and beetroot are particularly rich in inorganic nitrate . Dietary nitrate supplementation , via sequential reduction to nitrite and NO , has previously been shown to lower BP and improve endothelial function in healthy humans . We sought to determine if supplementing dietary nitrate with beetroot juice , a rich source of nitrate , will lower BP and improve endothelial function and insulin sensitivity in individuals with type 2 diabetes ( T2DM ) . Twenty-seven patients , age 67.2±4.9 years ( 18 male ) , were recruited for a double-blind , r and omized , placebo-controlled crossover trial . Participants were r and omized to begin , in either order , a 2-week period of supplementation with 250ml beetroot juice daily ( active ) or 250ml nitrate-depleted beetroot juice ( placebo ) . At the conclusion of each intervention period 24-h ambulatory blood pressure monitoring , tests of macro- and microvascular endothelial function , and a hyperinsulinemic isoglycemic clamp were performed . After 2 weeks administration of beetroot juice mean ambulatory systolic BP was unchanged : 134.6±8.4mmHg versus 135.1±7.8mmHg ( mean±SD ) , placebo vs active-mean difference of -0.5mmHg ( placebo-active ) , p=0.737 ( 95 % CI -3.9 to 2.8 ) . There were no changes in macrovascular or microvascular endothelial function or insulin sensitivity . Supplementation of the diet with 7.5mmol of nitrate per day for 2 weeks caused an increase in plasma nitrite and nitrate concentration , but did not lower BP , improve endothelial function , or improve insulin sensitivity in individuals with T2DM PURPOSE To determine the feasibility of measuring advanced glycated end-products (AGEs)from skin sample s and to evaluate the effects of a combination of vitamins E and C on measures of glycemic control and AGEs in patients with type 2 diabetes mellitus . METHODS Twenty-two patients with type 2 diabetes from a Family Medicine clinic were r and omly assigned to receive a daily dietary supplement containing either a combination of 400 mg of vitamin E and 500 mg of vitamin C or matching placebo for a period of one year . AGEs were measured from skin sample s taken from the buttock . RESULTS Nineteen subjects completed this one-year pilot study . There were no major problems found in measuring AGEs from skin sample s taken from the butttock . Neither the treatment or placebo group had significant changes in glycemic control , protein glycosylation or AGEs . DISCUSSION Skin sample s taken from the buttock area may be an appropriate site for the determination of AGE levels as this procedure appeared to be well-tolerated . Daily vitamin E and C supplementation did not improve measures of glycemic control or AGE levels in this small sample of patients with type 2 diabetes . Because antioxidant vitamins are inexpensive and free of side effects , additional research using a variety of antioxidant vitamin combinations and dosing regimens is needed Objective —The role of antioxidants in preventing vascular disease remains controversial . Vascular endothelial growth factor ( VEGF-A ) is important for endothelial and monocyte function . This study investigated the negative effects of smoking on monocyte migratory responsiveness to VEGF-A and the usefulness of vitamin C to prevent smoking-induced monocyte dysfunction . Methods and Results —The chemotactic response of isolated monocytes from a cohort of 17 non-smokers and 10 smokers toward VEGF-A was assessed . VEGF-A significantly stimulated the migration of monocytes in non-smokers ; the monocytes from smokers failed to respond to VEGF-A. Repeated analysis after 2 weeks of vitamin C intake ( 2g/d ) showed a fully restored VEGF-A – induced monocyte migration in smokers . VEGF-A serum levels were not altered by vitamin C.  VEGF-A – inducible kinase activity was intact in monocytes from smokers as assessed by in vitro kinase assay . Monocyte dysfunction can be mimicked in vitro by challenging monocytes with a range of reactive oxygen species ( ROS ) . Conclusions —Stimulation of monocyte migration by VEGF-A was severely attenuated in smokers , and the deficit observed was surmounted by vitamin C supplementation . The negative effects of smoking on monocyte function may translate into adverse impacts on VEGF-A – dependent repair processes such as arteriogenesis . These results propose a causative role of oxidative stress in smoking-induced monocyte dysfunction Endothelium-dependent vasodilation is impaired in humans with diabetes mellitus . Inactivation of endothelium-derived nitric oxide by oxygen-derived free radicals contributes to abnormal vascular reactivity in experimental models of diabetes . To determine whether this observation is relevant to humans , we tested the hypothesis that the antioxidant , vitamin C , could improve endothelium-dependent vasodilation in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus . We studied 10 diabetic subjects and 10 age-matched , nondiabetic control subjects .  Forearm blood flow was determined by venous occlusion plethysmography . Endothelium-dependent vasodilation was assessed by intraarterial infusion of methacholine ( 0.3 - 10 micrograms/min ) . Endothelium-independent vasodilation was measured by intraarterial infusion of nitroprusside ( 0.3 - 10 micrograms/min ) and verapamil ( 10 - 300 micrograms/min ) . Forearm blood flow dose-response curves were determined for each drug before and during concomitant intraarterial administration of vitamin C ( 24 mg/min ) . In diabetic subjects , endothelium-dependent vasodilation to methacholine was augmented by simultaneous infusion of vitamin C ( P = 0.002 ) ; in contrast , endothelium-independent vasodilation to nitroprusside and to verapamil were not affected by concomitant infusion of vitamin C ( P = 0.9 and P = 0.4 , respectively ) . In nondiabetic subjects , vitamin C administration did not alter endothelium-dependent vasodilation ( P = 0.8 ) . We conclude that endothelial dysfunction in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus can be improved by administration of the antioxidant , vitamin C. These findings support the hypothesis that nitric oxide inactivation by oxygen-derived free radicals contributes to abnormal vascular reactivity in diabetes OBJECTIVE Patients with systemic lupus erythematosus ( SLE ) experience excess morbidity and mortality due to coronary artery disease ( CAD ) that can not be fully explained by the classical CAD risk factors . Among emerging CAD risk factors , oxidative stress is currently being emphasized . We evaluated the effects of longterm antioxidant vitamins on markers of oxidative stress and antioxidant defense and endothelial function in 39 patients with SLE . METHODS Patients were r and omized to receive either placebo or vitamins ( 500 mg vitamin C and 800 IU vitamin E daily ) for 12 weeks . Markers of oxidative stress included malondialdehyde ( MDA ) and allantoin . Antioxidants measured included erythrocyte superoxide dismutase and glutathione peroxidase , plasma total antioxidant power ( as FRAP value ) , and ascorbic acid and vitamin E concentrations . Endothelial function was assessed by flow-mediated dilatation ( FMD ) of the brachial artery and plasma concentration of von Willebr and factor ( vWF ) and plasminogen activator inhibitor type 1 ( PAI-1 ) . Primary outcome of the study included the change in lipid peroxidation as revealed by MDA levels . Secondary outcomes included changes in allantoin and antioxidant levels and change in endothelial function . RESULTS After treatment , plasma ascorbic acid and alpha-tocopherol concentrations were significantly ( p < 0.05 ) increased only in the vitamin-treated group , associated with a significant decrease ( p < 0.05 ) in plasma MDA . Other oxidative stress markers and antioxidant levels remained unchanged in both groups . FMD and vWF and PAI-1 levels remained unchanged in both groups . CONCLUSION Combined administration of vitamins C and E was associated with decreased lipid peroxidation , but did not affect endothelial function in patients with SLE after 3 months of therapy AIMS Patients with type 2 diabetes ( T2DM ) and chronic kidney disease ( CKD ) have impaired endothelial function . Vitamin D and its analogs may play a role in regulation of endothelial function and inflammation . We studied effects of paricalcitol compared to placebo on endothelial function and markers of inflammation and oxidative stress in patients with T2DM and CKD . METHODS A double blind , r and omized , placebo-controlled trial was conducted in 60 patients with T2DM and stage 3 or 4 CKD .  Paricalcitol 1 mcg or placebo was administered orally once daily for three months . Brachial artery flow mediated dilatation ( FMD ) , nitroglycerine mediated dilation ( NMD ) , and plasma concentrations of inflammatory cytokines , tumor necrosis factor -α and interleukin-6 , highly-sensitive C-reactive protein ; endothelial surface proteins , intercellular adhesion molecule -1 and monocyte chemo attractant protein-1 , and plasma glucose , insulin , free fatty acids , and urinary isoprostane were measured at baseline and end of three months . RESULTS 27 patients in the paricalcitol group and 28 patients in the control group completed the study , though analysis of FMD at both time points was possible in 23 patients in each group . There was no significant difference in the change in FMD , NMD or the biomarkers examined after paricalcitol or placebo treatment . CONCLUSIONS Treatment with paricalcitol at this dose and duration did not affect brachial artery FMD or biomarkers of inflammation and oxidative stress . The lack of significance may be due to the fact that the study patients had advanced CKD and that effects of paricalcitol are not additive to the effects of glycemic , lipid and anti-hypertensive therapies Background —Hyperlipidemia is associated with endothelial dysfunction , an early event in atherosclerosis and predictor of risk for future coronary artery disease . Epidemiological studies suggest that increased dietary intake of antioxidants reduces the risk of coronary artery disease . The purpose of this study was to determine whether antioxidant vitamin therapy improves endothelial function and affects surrogate biomarkers for oxidative stress and inflammation in hyperlipidemic children . Methods and Results —In a r and omized , double-blind , placebo-controlled trial , the effects of antioxidant vitamins C ( 500 mg/d ) and E ( 400 IU/d ) for 6 weeks and the National Cholesterol Education Program Step II ( NCEP-II ) diet for 6 months on endothelium-dependent flow-mediated dilation ( FMD ) of the brachial artery were examined in 15 children with familial hypercholesterolemia ( FH ) or the phenotype of familial combined hyperlipidemia ( FCH ) .  Antioxidant vitamin therapy  improved FMD of the brachial artery compared with baseline ( P < 0.001 ) without an effect on biomarkers for oxidative stress ( autoantibodies to epitopes of oxidized LDL , F2-isoprostanes , 8-hydroxy-2′-deoxyguanosine ) , inflammation ( C-reactive protein ) , or levels of asymmetric dimethylarginine , an endogenous inhibitor of nitric oxide . Conclusions —Antioxidant therapy with vitamins C and E restores endothelial function in hyperlipidemic children . Early detection and treatment of endothelial dysfunction in high-risk children may retard the progression of atherosclerosis
Prolonged antioxidant vitamin E and /or C supplementation could be effective to improve endothelial function in non-obese T2DM subjects
Controversy exists among trials assessing whether prolonged antioxidant vitamin supplementation improves endothelial function in type 2 diabetes mellitus ( T2DM ) subjects .
The aim of this study was to systematic ally review and quantify the effect of antioxidant vitamin supplementation on endothelial function in T2DM subjects .