title: Chronic vitamin E administration improves brachial reactivity and increases intracellular magnesium concentration in type II diabetic patients. Effect of ascorbic acid on microcirculation in patients with Type II diabetes: a randomized placebo-controlled cross-over study. High-dose oral vitamin C partially replenishes vitamin C levels in patients with Type 2 diabetes and low vitamin C levels but does not improve endothelial dysfunction or insulin resistance. Vitamin C affects thrombosis/ fibrinolysis system and reactive hyperemia in patients with type 2 diabetes and coronary artery disease. The effect of vitamin E on endothelial function of micro- and macrocirculation and left ventricular function in type 1 and type 2 diabetic patients. Evaluation of the Local Effects of Vitamin E ( E-Mousse®) on Free Radicals in Diabetic Microangiopathy: A Randomized, Controlled Trial Effects of insulin lispro and chronic vitamin C therapy on postprandial lipaemia, oxidative stress and endothelial function in patients with type 2 diabetes mellitus. Effect of oral vitamin E (alpha-tocopherol) supplementation on vascular endothelial function in Type 2 diabetes mellitus. Lack of effect of oral vitamin C on blood pressure, oxidative stress and endothelial function in Type II diabetes. Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus. The effect of vitamin E on blood pressure in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled trial Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus.
abstract: Vascular disease accounts for the majority of the clinical complications in diabetes mellitus . As an exaggerated oxidative stress degree has been postulated as the link between diabetes mellitus and endothelial function , a possible positive effect of plasma vitamin E ( Vit . E ) administration on brachial reactivity could be postulated . Our study aims at investigating the possible effect of chronic Vit . E administration on brachial reactivity , oxidative stress indexes , and intracellular magnesium and calcium content in type II diabetic patients free of diabetic complications . Forty adult , type II diabetic patients were enrolled in the study , which was deigned as a double blind , r and omized vs. placebo trial . At baseline all patients underwent the following tests : 1 ) anthropometric and metabolic examinations , 2 ) evaluation of oxidative stress indexes , 3 ) intracellular magnesium and calcium measurements , and 4 ) determination of arterial compliance and distensibility . Then , all patients were r and omly assigned to Vit . E treatment at a dose of 600 mg/day ( Evion Forte ; n = 20 ) or placebo ( n = 20 ) over 8 weeks . At the end of this treatment period , a complete reevaluation of the patients was made . Vit . E treatment was associated with a significant improvement in the percent change in brachial artery diameter ( P<0.03 ) and oxidative stress indexes ( P < 0.005 ) . In the Vit . E group , the percent change in brachial artery diameter correlated positively with the percent change in oxidative stress indexes ( oxidized/reduced glutathione , Trolox-equivalent antioxidant capacity , thiobarbituric acid reaction products , lipid peroxides ) and intracellular cation content ( magnesium and calcium ) . After adjustment for age , sex , body mass index , and wait/hip ratio , all of these correlations remained significant ( P<0.03 for all ) . Furthermore , adjusting for glycosylated hemoglobin , plasma total cholesterol , and homeostatic model index , brachial artery diameter was still correlated with the percent change in oxidative stress indexes ( P<0.04 for all ) . Nevertheless , the relationship between the percent change in brachial artery diameter and oxidative stress indexes was no longer significant after adjustment for intracellular Mg and Ca2 + . In conclusion , our study demonstrates that chronic administration of Vit . E improves brachial artery reactivity in patients with type II diabetes mellitus . Such an effect seems mediated by a reduction in oxidative stress and a regulation of intracellular calcium and magnesium contents Manifestations of vascular disease , including microvascular changes , constitute the major part of the morbidity and mortality in diabetic patients . Oxidative stress has been suggested to play an important role in the vascular dysfunction of diabetic patients . Furthermore , epidemiological observations indicate a beneficial effect of an increased dietary intake of antioxidants . The present study tested the hypothesis that the antioxidant ascorbic acid influences microcirculatory function in patients with Type II diabetes . Patients with Type II diabetes were treated with 1 g of ascorbic acid three times a day for 2 weeks in a r and omized placebo-controlled double-blind cross-over design . Microvascular reactivity was assessed by  vital capillaroscopy  and PRH ( post-occlusive reactive hyperaemia ) . hs-CRP ( high-sensitivity C-reactive protein ) , IL-6 ( interleukin-6 ) , IL-1ra ( interleukin-1 receptor antagonist ) and ox-LDL ( oxidized low-density lipoprotein ) were analysed . The results showed no significant change in microvascular reactivity assessed after 2 weeks of ascorbic acid treatment . TtP ( time to peak ) was 12.0+/-3.3 s before and 11.2+/-3.5 s after ascorbic acid ( n=17 ) . In comparison , TtP was 11.5+/-2.9 s before and 10.6+/-2.8 s after placebo ( not significant ) . IL-1ra , IL-6 , hs-CRP and ox-LDL did not change significantly after ascorbic acid , neither as absolute or relative values . In conclusion , in contrast with some studies reported previously , we could not demonstrate an effect of continuous oral treatment with ascorbic acid on microvascular reactivity assessed at the level of individual capillaries . Furthermore , we found no indication of an effect on inflammatory cytokines or ox-LDL Endothelial dysfunction is a hallmark of Type 2 diabetes related to hyperglycemia and oxidative stress . Nitric oxide-dependent vasodilator actions of insulin may augment glucose disposal . Thus endothelial dysfunction may worsen insulin resistance . Intra-arterial administration of vitamin C improves endothelial dysfunction in diabetes . In the present study , we investigated effects of high-dose oral vitamin C to alter endothelial dysfunction and insulin resistance in Type 2 diabetes .  Plasma vitamin C levels in 109 diabetic subjects were lower than healthy ( 36 + /- 2 microM ) levels . Thirty-two diabetic subjects with low plasma vitamin C ( < 40 microM ) were subsequently enrolled in a r and omized , double-blind , placebo-controlled study of vitamin C ( 800 mg/day for 4 wk ) . Insulin sensitivity ( determined by glucose clamp ) and forearm blood flow in response to ACh , sodium nitroprusside ( SNP ) , or insulin ( determined by plethysmography ) were assessed before and after 4 wk of treatment . In the placebo group ( n = 17 subjects ) , plasma vitamin C ( 22 + /- 3 microM ) , fasting glucose ( 159 + /- 12 mg/dl ) , insulin ( 19 + /- 7 microU/ml ) , and SI(Clamp ) [ 2.06 + /- 0.29 x 10(-4 ) dl x kg(-1 ) x min(-1)/(microU/ml ) ] did not change significantly after placebo treatment . In the  vitamin C  group ( n = 15 subjects ) , basal plasma vitamin C ( 23 + /- 2 microM ) increased to 48 + /- 6 microM ( P < 0.01 ) after treatment , but this was significantly less than that expected for healthy subjects ( > 80 microM ) . No significant changes in fasting glucose ( 156 + /- 11 mg/dl ) , insulin ( 14 + /- 2 microU/ml ) , SI(Clamp ) [ 2.71 + /- 0.46 x 10(-4 ) dl x kg(-1 ) x min(-1)/(microU/ml ) ] , or forearm blood flow in response to ACh , SNP , or insulin were observed after vitamin C treatment . We conclude that high-dose oral vitamin C therapy , result ing in incomplete replenishment of vitamin C levels , is ineffective at improving endothelial dysfunction and insulin resistance in Type 2 diabetes OBJECTIVE To examine the effect of vitamin C on forearm vasodilatory response to reactive hyperemia and on plasma level of plasminogen activator inhibitor 1 ( PAI-1 ) , von Willebr and factor ( vWF ) , tissue plasminogen activator ( tPA ) , antithrombin III ( ATIII ) , proteins C and S , and factors V ( fV ) and VII ( fVII ) in patients with both type 2 diabetes and CAD . RESEARCH DESIGN AND METHODS A total of 39 patients with type 2 diabetes and CAD were divided into two groups and received vitamin C ( 2 g/day ) or no antioxidant for 4 weeks . Forearm blood flow was determined using venous occlusion gauge-strain plethysmography at baseline and after treatment . Forearm vasodilatory response to reactive hyperemia ( RH% ) or nitrate ( NTG% ) was defined as the percent change of flow from baseline to the maximum flow during reactive hyperemia or after administration of nitrate , respectively . Biochemical markers were determined by enzyme-linked immunosorbent assay ( ELISA ) or other st and ard methods . RESULTS RH% was significantly increased after treatment with vitamin C ( from 62.4 + /- 7.2 to 83.1 + /- 9.3 % , P = 0.024 ) but remained unaffected in the control group . Vitamin C decreased plasma levels of fV ( from 143 + /- 5.4 to 123 + /- 6.03 % , P = 0.038 ) , vWF ( from 133.5 + /- 14.5 to 109.5 + /- 11.4 % , P = 0.016 ) , and tPA ( from 12.3 + /- 0.99 to 8.40 + /- 0.60 ng/ml , P = 0.001 ) , whereas these levels remained unaffected in the control group . The changes in RH% , vWF , and tPA were significantly greater ( P = 0.028 , 0.036 , and 0.007 , respectively ) in the vitamin C-treated group than in the control group . Levels of ATIII , proteins S and C , fVII , and PAI-1 remained unchanged in all groups . CONCLUSIONS Short-term treatment with high doses of vitamin C improved RH% and decreased plasma levels of tPA and vWF in patients with type 2 diabetes and CAD We examined the effects of high-dosage vitamin E treatment over a 12-month period on the vascular reactivity of micro- and macrocirculation and left ventricular function in diabetic patients . Subjects ( n = 89 ) were r and omized to vitamin E ( 1,800 IU daily ) or placebo and were followed for 12 months . High-resolution ultrasound images were used to measure the flow-mediated dilation ( FMD ; endothelium dependent ) and nitroglycerin-induced dilation ( NID ; endothelium independent ) of the brachial artery . Laser Doppler perfusion imaging was used to measure vascular reactivity in the forearm skin . Left ventricular function was evaluated using transthoracic echocardiogram . At the end of the 6-month period , a worsening in endothelium-dependent skin vasodilation ( P = 0.02 ) and rise in endothelin levels ( P = 0.01 ) were found in the vitamin E compared with the placebo group . At the end of the 12-month period , a worsening was observed in NID ( P = 0.02 ) and a marginal worsening was seen in systolic blood pressure ( P = 0.04 ) and FMD ( P = 0.04 ) in the vitamin E compared with the placebo group . In addition C-reactive protein levels decreased marginally in the vitamin E compared with the placebo group ( P = 0.05 ) . No changes were observed in left ventricular function . We concluded that long-term treatment with 1,800 IU of vitamin E has no beneficial effects on endothelial or left ventricular function in diabetic patients . Because vitamin E-treated patients had a worsening in some vascular reactivity measurements when compared with control subjects , the use of high dosages of vitamin E can not be recommended The aims of the study were to evaluate the short-term effects of a new thermosensitive , vitamin E ( V-E ) mousse on local free radicals ( FR ) and skin flux in diabetic microangiopathy . A group of 40 patients with diabetic microangiopathy was included . The variation in measure ments of skin FR was evaluated by the D-Rom test . Subjects were between 45 and 65 years with type II diabetes and good metabolic control .  E-mousse ® , a thermoactive preparation of acetate vitamin E ( 20 % ) , was applied twice daily on the whole surface of the leg ( below knee ) and foot for 3 weeks . The contralateral leg was untreated acting as control .  Subjects with age between 45 and 65 years with type II diabetes ( diagnosed at least 5 years before ) and good metabolic control ( blood sugar < 180 mg/dL ) were included after informed consent . Patients with uncontrolled diabetes , peripheral vascular disease , and severe lower limbs infec tions were excluded .  Local free radicals ( FR ) and laser Doppler flux including the venoarteriolar response ( VAR ) were evaluated . The tolerability was evaluated by a semiquantitative score . Of the 40 included patients 34 completed the study . The 2 groups were comparable . At 3 weeks there was no decrease in FR in controls ; the decrease in the treatment group was 45.3 % ( p < 0.05 ) . Also in the treatment group RF decreased ( p < 0.05 ) and the VARveno improved from an average of 21 % to an average of 38 % ( p < 0.05 ) . No significant variations were observed in the control group . The variation in symptomatic score was from a total value of 8 to 5 in the control group and from 8 to 1 in the treatment group ( p < 0.02 ) . Their tolerability was good . In conclusion local treatment with E-mousse for 3 weeks in diabetic microangiopathy improves skin microcirculation and the metabolic condition as shown by the decrease in FR BACKGROUND Insulin therapy may influence cardiovascular disease ( CVD ) and lipid metabolism in type 2 diabetes ( T2D ) . Exaggerated postpr and ial lipaemia ( PPL ) is a feature of diabetic dyslipidaemia affecting CVD via enhanced oxidative stress ( OS ) and endothelial dysfunction . We assessed endothelial function and OS during PPL following insulin and vitamin C.  Twenty ( 17 M ) T2D patients were studied ( mean Hba1c 8.4 % ) at baseline , following 6 weeks of insulin lispro ( 0.2 Iu kg-1 ) and vitamin C 1-g  daily . Eight-h  lipid and glucose profiles were measured following a fatty meal .  Endothelial function ( flow-mediated vasodilatation : FMD ) and OS were measured at fasting , 4 h and 8 h. MATERIAL S AND METHODS Glucose , body mass index , and total and LDL cholesterol remained unchanged . FMD improved . Placebo group : fasting , 1.1 + /- 1.2 to 4.2 + /- 1.1 % ( P < 0.001 ) ; 4-h , 0.3 + /- 1.2 to 3.1 + /- 0.9 % ( P < 0.01 ) ; 8-h , 0.7 + /- 1.1 to 3.76 + /- 1.1 % ( P < 0.001 ) . Vitamin C group : fasting , 0.9 + /- 1.1 to 6.1 + /- 1.3 % ( P < 0.001 ) ; 4-h , 0.7 + /- 1.5 to 4.9 + /- 2.1 % ( P < 0.001 ) ; 8-h , 0.8 + /- 0.9 to 5.8 + /- 0.6 % ( P < 0.01 ) . Post-pr and ial lipaemia was attenuated : TG area-under-curve ( mmol L-1 8 h-1 ) , 52.6 + /- 11 to 39.1 + /- 12.5 ( placebo group ) , P < 0.02 ; and 56.9 + /- 8 to 40.1 + /- 10.3 ( vitamin C group ) , P < 0.02 . Oxidative stress was reduced , with greater changes in the vitamin C group . CONCLUSION Insulin may thus exert vascular benefits in T2D , by modifying fasting and postpr and ial lipid metabolism result ing in reduced OS and improved EF . Vitamin C therapy may augment the vascular benefits of insulin in T2D through additional effects on OS and EF 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 Type II diabetes is characterized by increased oxidative stress , endothelial dysfunction and hypertension . We investigated whether short-term treatment with oral vitamin C reduces oxidative stress and improves endothelial function and blood pressure in subjects with Type II diabetes . Subjects ( n = 35 ) received vitamin C ( 1.5 g daily in three doses ) or matching placebo for 3 weeks in a r and omized , double-blind , parallel-group design . Plasma concentrations of 8-epi-prostagl and in F(2alpha ) ( 8-epi-PGF(2alpha ) ) , a non-enzymically derived oxidation product of arachidonic acid , were used as a marker of oxidative stress . Endothelial function was assessed by measuring forearm blood flow responses to brachial artery infusion of the endothelium-dependent vasodilator acetylcholine ( with nitroprusside as an endothelium-independent control ) and by the pulse wave responses to systemic albuterol ( endothelium-dependent vasodilator ) and glyceryl trinitrate ( endothelium-independent vasodilator ) . Plasma concentrations of vitamin C  increased from 58+/-6 to 122+/-10 micromol/l after vitamin C , but 8-epi-PGF(2alpha ) levels ( baseline , 95+/-4 pg/l ; after treatment , 99+/-5 pg/l ) , blood pressure ( baseline , 141+/-5/80+/-2 mmHg ; after treatment , 141+/-5/81+/-3 mmHg ) and endothelial function , as assessed by the systemic vasodilator response to albuterol and by the forearm blood flow response to acetylcholine , were not significantly different from baseline or placebo . Thus treatment with vitamin C ( 1.5 g daily ) for 3 weeks does not significantly improve oxidative stress , blood pressure or endothelial function in patients with Type II diabetes 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 Objective Oxidative stress has been suggested to play a role in the development of diabetes , hypertension and vascular dysfunction . Vitamin E , a major lipid-soluble dietary antioxidant , has two major dietary forms , α-tocopherol and γ-tocopherol . The potential importance of γ-tocopherol has largely been overlooked . Our aim was to investigate the effect of α-tocopherol and γ-tocopherol supplementation on 24-h ambulatory blood pressure ( BP ) and heart rate , vascular function and oxidative stress in individuals with type 2 diabetes . Method Fifty-eight individuals with type 2 diabetes were r and omized in a double-blind , placebo-controlled trial . Participants were r and omized to a daily dose of 500 mg/day RRR-α-tocopherol , 500 mg/day mixed tocopherols ( 60 % γ-tocopherol ) or placebo for 6 weeks . Primary endpoints were 24-h ambulatory BP and heart rate , endothelium-dependent and independent vasodilation and plasma and urinary F2-isoprostanes . Results Treatment with α-tocopherol significantly increased systolic BP [ 7.0 ( 5.2 , 8.8 ) mmHg , P < 0.0001 ] , diastolic BP [ 5.3 ( 4.0 , 6.5 ) mmHg , P < 0.0001 ] , pulse pressure [ 1.8 ( 0.6 , 3.0 ) mmHg , P < 0.005 ] and heart rate [ 2.0 ( 0.6 , 3.3 ) bpm , P < 0.005 ] versus placebo . Treatment with mixed tocopherols  significantly increased systolic BP [ 6.8 ( 4.9 , 8.6 ) mmHg , P < 0.0001 ] , diastolic BP [ 3.6 ( 2.3 , 4.9 ) mmHg , P < 0.0001 ] , pulse pressure [ 3.2 ( 2.0 , 4.4 ) mmHg , P < 0.0001 ] and heart rate [ 1.8 ( 0.5 , 3.2 ) bpm , P < 0.01 ] versus placebo . Treatment with α-tocopherol or mixed tocopherols  significantly reduced plasma F2-isoprostanes versus placebo , but had no effect on urinary F2-isoprostanes . Endothelium-dependent and independent vasodilation was not affected by either treatment . Conclusion In contrast to our initial hypothesis , treatment with either α- or mixed tocopherols  significantly increased BP , pulse pressure and heart rate in individuals with type 2 diabetes 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
target: Prolonged antioxidant vitamin E and /or C supplementation could be effective to improve endothelial function in non-obese T2DM subjects
background: 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 .