Dietary vitamin C and E modulates antioxidant levels in blood, brain, liver, muscle, and testes in diabetic aged rats

While tissue dysfunction is a well-recognized consequence of diabetes mellitus in aged people, the underlying mechanisms are poorly understood. Daily (VCE) supplementation of vitamins C and E can be beneficial to diabetic aged animals in reducing free radical production. The aim of this study was to investigate whether dietary VCE supplementation modulates oxidative stress and antioxidant redox systems in streptozotocin (STZ)-induced aged diabetic rats. Thirty aged rats (18 - 20 months) were randomly divided into three groups. The first group acted as a control and the second group was diabetic. VCE-supplemented feed was given to aged, diabetic rats, constituting the third group. Diabetes was induced using a single dose of intraperitoneal STZ. On the 21(st) day after STZ dosage, blood and tissue samples were taken from all animals. Glutathione peroxidase activity in liver, erythrocytes, muscle, and testes; catalase activity in plasma and erythrocytes; reduced glutathione levels in plasma; vitamin E concentration in plasma, liver, and muscle; b-carotene concentration in brain; and high-density lipoprotein (HDL)-cholesterol levels in plasma were lower in the diabetic group than in the control group. Lipid peroxidation (LP) levels in plasma, liver, brain, and muscle, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), triacyglycerols, and total and low-density lipoprotein (LDL)-cholesterol values in plasma were higher in the diabetic group than in the control group. The LP, enzyme, vitamin, and lipid profile values levels were mostly restored by VCE treatment. Liver and testis weights did not change by diabetic status and VCE supplementation, although body weight was lower in the diabetic group than in the control group. In conclusion, brain, liver, and testes tissues seem most sensitive in aged diabetic rats to oxidative stress. We observed that VCE supplementation relieves oxidative stress in the blood and tissues of diabetic aged rats by modulating the antioxidant system and lipid profile.     

Vitamin c and aloe vera supplementation protects from chemical hepatocarcinogenesis in the rat

The effects of vitamin C and aloe vera gel extract supplementation on induced hepatocarcinogenesis in male Sprague-Dawley rats (120–150 g) by diethylnitrosamine (DEN) and 2-acetylaminofluorene (AAF) was investigated. The severity of the carcinogenesis process was determined by measuring γ-glutamyl transpeptidase (GGT) and the placental form of glutathione S-transferase (GSTP) histochemically in situ and in plasma and liver fractions. In addition, plasma alkaline phosphatase (ALP) and liver microsomal uridine diphosphate glucuronyl transferase (UDPGT) activity were also determined. Administration of DEN/AAF caused an increase in the surface area and number of enzyme-positive foci (both GGT and GSTP) compared with control. Supplementation of vitamin C or aloe vera gel extract to the cancer-induced rats suppressed this increase significantly (P < 0.05; P < 0.001). Increases in liver UDPGT, GGT, and GSTP activities were also observed with cancer induction that were again suppressed with either vitamin C or aloe vera gel supplementation. Plasma GGT in the DEN/AAF rats were determined monthly for the duration of the experiment and found to be reduced as early as 1 mo with aloe vera gel supplementation and 2 mo with vitamin C supplementation. In conclusion, vitamin C and aloe vera gel extract supplementation were found to be able to reduce the severity of chemical hepatocarcinogenesis.     

Nutritional supplement attenuates selected oxidative stress markers in pediatric patients with cystic fibrosis

Our aim was to test the hypothesis that nutritional supplement (AquADEKs; Axcan Scandipharm Inc., Birmingham, Ala, USA) with various pharmaceutical forms of such as chewable tablets, capsules, and liquid administered daily for 12 weeks would reduce oxidative stress and enhance antioxidant status in pediatric patients with cystic fibrosis (CF). A total of 50 patients with CF and 21 healthy children were included in the study. Patients were divided into 4 groups: group A received supplementation with vitamins A (3 mg daily), E (200 mg daily), and D₃ (20 μg daily); group B was supplemented with AquADEKs chewable tablets; group C received the recommended amount of AquADEKs capsules; and group D was supplemented with AquADEKs liquid. The level of oxidative stress was determined by the analysis of activities of enzymes neutralizing reactive oxygen species and by the estimated markers of intensity of free radical processes. There was no difference in the activity of erythrocyte catalase, hydroperoxides level, and sulfhydryl group content in blood plasma between patients with CF and healthy children. The plasma total antioxidant status was decreased in all CF groups compared with the control. The supplementation with either AquADEKs chewable tablets or capsules normalized the malondialdehyde level in plasma. AquADEKs in various pharmaceutical forms normalized the sulfhydryl group content of erythrocytes. The superoxide dismutase activity was increased to near control level in the patients supplemented with either AquADEKs chewable tablets or liquid as compared with the group supplemented with vitamins or with AquADEKs capsules. In conclusion, AquADEKs attenuates selected oxidative stress markers in pediatric patients with CF.     

锰接触对大鼠肝脏的影响

目的探讨锰接触对大鼠肝脏功能和病理组织学的影响。方法SD大鼠36只随机分为3组,每组12只。高、低剂量染锰组分别给予含二氯化锰5.0g/L和0.5g/L的水溶液自由饮食,对照组给予蒸馏水。持续60天后,每组取9只动物应用荧光分光光度法测定各组动物肝脏匀浆的丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、碱性磷酸酶(ALP)活性和蛋白质含量;另3只动物作肝组织切片,HE法染色,光镜下检测肝组织病理学的变化。结果(1)与对照组相比,高、低剂量染锰组肝脏匀浆ALT、AST、ALP的活性明显升高,高剂量组为(60.79±9.88)、(49.77±8.36)和(49.43±8.88)U/ml,P<0.01;低剂量组为(47.35±8.11)、(37.31±6.77)和(32.34±4.53)U/ml,上述各项变化均呈现显著的量-效关系(P<0.05);而PRO含量各组间无显著差异(P>0.0)。(2)高、低剂量染锰组肝脏组织学损害主要表现为不同程度的肝小叶结构紊乱、肝细胞索松散、肝细胞脂肪变性和粒细胞浸润。结论锰接触对大鼠肝脏功能和组织学产生了明显的损害。     

Natural antioxidants protect against lead-induced damage during pregnancy and lactation in rat's pups

The aim of this study was to add further evidence to the biochemical changes produced in lead-exposed pups and to investigate the potential role of natural antioxidants against the lead-induced damage. Pregnant Wistar rats received treatments with drinking water, divided into four groups, as follows: (1) distilled water; (2) lead (300 mg/L); (3) lead+Zn (20 mg/L)+vitamins A (50,000 U/L), C (2 g/L), E (500 mg/L) and B₆ (500 mg/L); and (4) vitamins+Zn solution. We found a significant decrease in haemoglobin and haematocrit values as well and an increase in haemolysis among lead-exposed pups. Vitamins and zinc supplementation were effective in restoring δ-aminolevulinic acid dehydratase, inhibited by lead in erythrocytes, but did not reach control values. Lead exposure increased the production of thiobarbituric acid reactive substances (TBARS) and catalase activity in kidneys and liver that were reduced by the co-administration of vitamins and zinc. Our findings suggest that administration of antioxidants during gestation and lactation could prevent some of the negative effects of lead.     

Effect of spinal cord transection on plasma and hepatic levels of certain essential elements and vitamins in rats

This study was conducted to determine whether spinal cord transection produces nutritional deficiency states in certain essential elements and water soluble vitamins in the rat. Spinal cords of female rats were severed at the T-9 level and these animals were matched and pair-fed to control animals that had undergone sham surgery. Following periods of 60, 90 and 180 days, animals were sacrificed and their plasma and livers assayed for selenium, manganese, zinc and magnesium and eight water soluble vitamins. The results indicate that spinal cord injury did not cause deficiencees in those nutrients studied. Instead the cord transection produced accumulations in the liver of all the elements and six of the vitamins studied. No explanation for these accumulations is known at this time.     

Effects of dietary vitamin E and high supplementation of vitamin C on plasma glucose and cholesterol levels

Weanling male Sprague Dawley rats were fed ad libitum a purified basal diet free of vitamins E and C. In Experiment I (4 weeks), 24 rats were divided into four groups with 2×2 factorial design. They were supplemented with 0 or 45 IU/kg diet of vitamin E, and O or 2.0 g/kg diet of vitamin C. In Experiment II (16 weeks), 36 rats were divided into six groups with 2×3 factorial design. Vitamin E was supplemented at the level of O or 45 IU/kg diet, and vitamin C was supplemented at the level of O, 1.5, or 3.0 g/kg diet, respectively. Plasma glucose level and cholesterol level were determined in both experiments. The plasma levels of glucose and cholesterol were significantly and negatively correlated. Plasma glucose level was significantly increased and plasma cholesterol level significantly decreased by the high supplementation of vitamin C with or without vitamin E in the diet. Vitamin E deficiency decreased plasma glucose level and increased plasma cholesterol level significantly with or without vitamin C supplementation. The groups with adequate level of vitamin E (45 IU/kg diet) and no vitamin C showed moderate plasma glucose and cholesterol levels.     

Effect of manganese on certain enzymes and constituents of blood and serum in rabbits. II

Glutathione, glutathione reductase, urea, and manganese in blood; glutathione peroxidase and glucose-6-phosphate dehydrogenese in erythrocytes; total and free cholesterol in serum; and copper, manganese, and zinc in plasma were estimated in rabbits administered 0.30 mmole Mn²⁺/kg orally for 6 months in order to find a suitable biological indicator of early manganese poisoning. Significant increases in blood manganese, serum total cholesterol, and plasma copper were observed throughout the period of investigation while either transient or no alterations were found in other parameters.     

Vitamin B-6 metabolic enzymes in blood and placenta of pregnant mice

Plasma pyridoxal 5'-phosphate (PLP) concentrations decrease 50% in pregnant mice and erythrocyte PLP levels increase threefold over nonpregnant levels. These studies were designed to determine whether changes in the enzymes involved in synthesis and degradation of PLP in blood are altered during pregnancy. We measured net synthesis of PLP in erythrocytes and the activity of enzymes involved in the regulation of plasma and erythrocyte PLP concentration: erythrocyte pyridoxal kinase (PLK) and neutral phosphatase, and plasma and tissue alkaline phosphatase (ALP). Net synthesis of PLP and activities of erythrocyte PLK and neutral phosphatase in erythrocytes remained unchanged during pregnancy. We were unable to detect any dephosphorylation of PLP in erythrocytes of pregnant or nonpregnant mice. Mouse erythrocytes were devoid of ALP activity; neutral phosphatase was inactive with PLP and PLP was an uncompetitive inhibitor of the enzyme. Plasma ALP activity decreased 50% in the pregnant mice; therefore, it likely does not participate in the reduction of plasma PLP levels during pregnancy. Placenta had high levels of PLP-phosphatase activity (ALP) and, if it is active as an ectoenzyme in this tissue as it is in others, it may be the most important mediator of plasma PLP levels in pregnancy.     

A randomized study to establish the effects of spirulina in type 2 diabetes mellitus patients

Spirulina is a microscopic and filamentous cyanobacterium that contains essential amino acids, essential fatty acids, vitamins, minerals and anti-oxidative components. The purpose of this study was to examine effects of spirulina intervention in Korean patients with type 2 diabetes. The subjects were 37 type 2 diabetic patients who visited a diabetic clinic in Seoul and randomly assigned into spirulina (8 g/day) or control group. During the intervention period of 12 weeks, subjects were asked to keep usual diet and prohibited to take any functional foods or dietary supplements. Spirulina supplementation for 12 weeks did not affect anthropometric parameters, however, lowered plasma triglycerides level significantly (p<0.05). Spirulina supplementation also resulted in a significant reduction in plasma malondialdehyde level (p<0.05) and an increase in plasma adiponectin level (p<0.1). The lipid lowering effect of spirulina supplementation was different according to serum lipid levels of the subjects before entering the intervention. The subjects with higher initial triglyceride level showed higher reduction in plasma triglyceride and blood pressure. The subjects with higher initial total cholesterol and LDL-cholesterol level showed higher reduction in plasma concentrations of total cholesterol, LDL-cholesterol, IL-6, and blood pressure. It seems that spirulina supplementation is more effective in subjects with dyslipidemia. This study provides the evidence for beneficial effects of spirulina supplementation on blood lipid profiles, inflammatory variables, and antioxidant capacity in Korean patients with type 2 diabetes. The results suggest that spirulina is a promising agent as a functional food for diabetes management.     

Oral Magnesium Supplementation for Treating Glucose Metabolism Parameters in People with or at Risk of Diabetes: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials

There is a large and growing body of literature focusing on the use of oral magnesium (Mg) supplementation for improving glucose metabolism in people with or at risk of diabetes. We therefore aimed to investigate the effect of oral Mg supplementation on glucose and insulin-sensitivity parameters in participants with diabetes or at high risk of diabetes, compared with a placebo. Several databases were searched investigating the effect of oral Mg supplementation vs placebo in patients with diabetes or conditions at high risk of diabetes. Data were reported as standardized mean differences (SMDs) with their 95% confidence intervals (CIs) using follow-up data of glucose and insulin-sensitivity parameters. Compared with placebo, Mg supplementation reduced fasting plasma glucose in people with diabetes. In people at high risk of diabetes, Mg supplementation significantly improved plasma glucose per se, and after a 2 h oral glucose tolerance test. Furthermore, Mg supplementation demonstrated an improvement in insulin sensitivity markers. In conclusion, Mg supplementation appears to have a beneficial role and improves glucose parameters in people with diabetes. Moreover, our work indicates that Mg supplementation may improve insulin-sensitivity parameters in those at high risk of diabetes.     

Magnesium proteinate is more protective than magnesium oxide in heat-stressed quail

We evaluated the effects of dietary supplementation with Mg-oxide and Mg-proteinate on performance; nutrient digestibilities; malondialdehyde (MDA) concentrations in serum, liver, and thigh meat; and serum cholesterol and triacylglycerol concentrations in Japanese quail (Coturnix coturnix japonica) exposed to high ambient temperature. The birds (n = 360; 10 d old) were randomly assigned to 12 treatment groups consisting of 6 replicates of 5 birds each in a 2 x 2 x 3 factorial arrangement (temperature, Mg source, Mg level). Birds were maintained in temperature-controlled rooms at 22 degrees C for 24 h/d or 34 degrees C for 8 h/d (0900-1700 h) and fed a basal diet or that diet supplemented with 1 or 2 g Mg-oxide or Mg-proteinate/kg of diet. Heat exposure decreased (P = 0.0001) live weight gain, feed intake, feed efficiency, and carcass weight in quail fed the basal diet. A linear increase in feed intake (P = 0.008) and body weight (P = 0.001), and improvements in feed efficiency (P = 0.001), carcass weight (P < 0.0001), digestibility of dry matter, organic matter, crude protein, and ether extract were found in Mg-supplemented, heat-stressed quail. The effects of Mg-proteinate were greater than those of Mg-oxide (P < or = 0.0001). Serum Mg (P = 0.001) concentration increased, whereas the concentration of MDA in serum (P = 0.0001), liver (P = 0.04), and thigh meat (P = 0.0001) and serum triglyceride and cholesterol concentrations decreased linearly (P = 0.001) with the level of Mg in the diet. Interactions between dietary Mg source, temperature, and level of supplementation (P < or = 0.05) were found for several variables. Results of the present study suggest that supplementation with Mg-proteinate is more protective than Mg-oxide in reducing the negative effects of heat stress in quail.     

Dietary supplementation of glycine modulates inflammatory response indicators in broiler chickens

Three experiments were conducted to investigate the effect of dietary glycine (Gly) supplementation on inflammatory responses in broiler chicks fed a basal diet using maize and soybean meal as the primary ingredients. Inflammation-related processes following lipopolysaccharide (LPS) injection were examined by analysing plasma concentrations of nitrate plus nitrite (NOx) and ceruloplasmin (Cer) in experiments 1 and 2, or expression of several genes in the spleen and liver including IL-1 beta and -6, TNF-like ligand (TL)1A, inducible NO synthase, interferon (IFN)-gamma and toll-like receptor (TLR) 4 were examined in experiment 3. Growth performance was also determined following immunological stimulation by both LPS and Sephadex injection in experiment 2. In experiment 1, birds fed a diet supplemented with Gly at 10 or 20 g/kg showed lower responses in plasma NOx and Cer than birds fed the diet supplemented with Gly at 0 or 40 g/kg. In experiment 2, a similar effect of Gly supplementation at 10 g/kg on plasma NOx and Cer was observed when chicks were fed either an isonitrogenous diet with Gly or glutamic acid (Glu). Gly-supplemented diet-fed birds showed better growth performance than Glu-supplemented diet-fed birds. The splenic expression of inflammatory response-related genes in birds fed a diet supplemented with Gly at 10 g/kg diet was lower than that of birds fed the basal diet in experiment 3. These results suggest that dietary Gly supplementation modulates the inflammatory response partly through changes in the expression of pro-inflammatory cytokines such as IL-1, IL-6, IFN-gamma and TL1A.     

Magnesium deficiency modulates the insulin signaling pathway in liver but not muscle of rats

Altered insulin secretion and sensitivity have been observed in Mg-deficient animals. However, the effects of Mg deficiency and supplementation on intracellular signaling events triggered by insulin are unknown. Therefore, we studied the early steps of insulin action in muscle and liver of rats fed Mg-deficient (DF-6, DF-11) or control (CO-6, CO-11) diets for 6 or 11 wk, respectively, and Mg-deficient or control diets for 6 wk, followed by Mg supplementation for 5 wk (SDF and SCO groups, respectively). There were no differences in the glucose disappearance rate (K(itt)) or insulin signaling between CO-6 and DF-6 rats. Between the two groups of rats fed for 11 wk, the DF-11 group had a significantly greater K(itt). SDF and SCO rats had K(itt) that did not differ from CO-11 rats, but that were significantly lower than in DF-11 rats. In the latter rats, insulin receptor and insulin receptor substrate-1 protein and phosphorylation levels were elevated in liver and there was a greater association between the insulin receptor substrate-1 and p85 subunit of phosphatidyl-inositol 3-kinase compared with CO-11 rats. There were no differences in the early steps of insulin action in SDF and control rats. These results suggest that the normal insulin sensitivity maintained by Mg supplementation and the increased insulin sensitivity produced by a long period of Mg deprivation may result, at least in part, from alterations in or maintenance of the early molecular steps of insulin action in hepatic tissue.     

Effects of antioxidant vitamins on newborn and placental traits in gestations at high altitude: comparative study in high and low altitude native sheep

The present study evaluated the hypothesis that the effects of hypoxia on sheep pregnancies at high altitude (HA) are mediated by oxidative stress and that antioxidant vitamins may prevent these effects. Both HA native and newcomer ewes were maintained at an altitude of 3,589 m during mating and pregnancy. Control low altitude (LA) native ewes were maintained at sea level. Half of each group received daily oral supplements of vitamins C (500 mg) and E (350 IU) during mating and gestation. Near term, maternal plasma vitamin levels and oxidative stress biomarkers were measured. At delivery, lambs were weighed and measured, and placentas were recovered for macroscopic and microscopic evaluation. Vitamin concentrations in supplemented ewes were two- or threefold greater than in non-supplemented ewes. Plasma carbonyls and malondialdehyde in non-supplemented ewes were consistent with a state of oxidative stress, which was prevented by vitamin supplementation. Vitamin supplementation increased lamb birthweight and cotyledon number in both HA native and newcomer ewes, although placental weight and cotyledon surface were diminished. Placentas from vitamin-supplemented HA ewes were similar to those from ewes at sea level, making these placental traits (weight, number and diameter of cotyledons) similar to those from ewes at sea level. Vitamin supplementation had no effect on LA pregnancies. In conclusion, supplementation with vitamins C and E during pregnancy at HA prevents oxidative stress, improving pregnancy outcomes.     

Antioxidant effect of Hemidesmus indicus on ethanol-induced hepatotoxicity in rats

The antioxidant effect of the ethanolic root extract of Hemidesmus indicus, an indigenous Ayurvedic medicinal plant used in soft drinks in India, was studied in rats with ethanol-induced hepatotoxicity. Administering 20% ethanol (5 g/kg of body weight/day) for 60 days to male Wistar rats resulted in significantly decreased body weight and increased liver/body weight ratio. The liver marker enzymes, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatae (ALP), gamma-glutamyl transpeptidase (GGT), and lactate dehydrogenase (LDH), were elevated. In addition, the levels of plasma, erythrocyte, and hepatic thiobarbituric acid-reactive substances (TBARS), hydroperoxides (LOOH), and conjugated dienes (CD) were also elevated in ethanol-fed rats as compared to those of the experimental control rats. Decreased activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), vitamin C, and alpha-tocopherol (vitamin E) were also observed in ethanol-administered as compared to control rats. Ethanolic root extract of H. indicus was administered at a dose of 500 mg/kg of body weight/day for the last 30 days of the experiment to rats with ethanol-induced liver injury, which significantly increased body weight, significantly decreased the liver/body weight ratio, AST, ALT, ALP, GGT, and LDH activities, and also the levels of TBARS, LOOH, and CD, significantly elevated the activities of SOD, CAT, GPx, and GSH in plasma, erythrocytes, and liver, and also increased levels of plasma and liver vitamin C and vitamin E at the end of the experimental period as compared to those of untreated ethanol-administered rats. Thus, our data indicate that treatment with H. indicus extract offers protection against free radical-mediated oxidative stress in plasma, erythrocytes, and liver of animals with ethanol-induced liver injury.     

铝螯合剂对染铝大鼠肝酶谱及必需元素影响

目的探讨铝螫合剂1，2-二甲基-3-羟基-4-吡啶酮（DHPO）对铝染毒大鼠血清谷丙转氨酶（ALT）、谷草转氨酶（AST）、碱性磷酸酶（ALP）及肝脏中铝、锌、铜、铁、钙、镁等元素的影响。方法 AlCl3染毒Wistar大鼠3周后分别给予不同剂量的DHPO1周，测定血清ALT、AST、ALP活力及肝脏中铝、锌、铜、铁、钙、镁等元素含量。结果各组大鼠的ALT活力比较差异均无统计学意义（P〉0.05）；低、中、高剂量组的AST活力显著低于模型组（P〈0．01）；低剂量组ALP活力与模型组比较差异有统计学意义（P〈0．01）；Al含量测定结果显示：低、中、高剂量组均显著低于模型组（P〈0．01），且含量呈下降趋势，中、高剂量组的大鼠肝脏中锌、铜、铁、钙、镁的含量与阴性对照组比较差异均无统计学意义（P〉0.05）。结论DHPO在促进排铝的同时，对肝脏中锌、铜、铁、钙、镁含量无影响，且在一定剂量范围内对AST、ALP活力具有恢复作用。     

The effect of 7 to 8 months of vitamin/mineral supplementation on the vitamin and mineral status of athletes.

Blood indicators of eight vitamins (B1, B2, B6, C, E, A, B12, folate) and six minerals (Cu, Mg, Zn, Ca, P, Al) were measured in 86 athletes before and after a 7- to 8-month period of training. During this period half consumed a multivitamin/mineral supplement and a matched group took a placebo. Following the supplementation period, blood biochemical indicators of B1, B6, B12, and folate status all increased but there were no significant effects of supplementation on B2, C, E, and A, or on the blood levels of any of the minerals. The supplementation had no effect on red or white cell counts or on hemoglobin levels. Irrespective of the supplementation, some blood measures varied according to sex, females evidencing significantly higher values than males for vitamins C, E, copper, magnesium, and aluminium, with B2 being higher in males. It is concluded that 7 to 8 months of multivitamin/mineral supplementation increased the blood nutritional status of some vitamins but did not affect any blood mineral levels, and that some blood nutritional indicators may vary according to sex.     

Dietary L-arginine supplementation enhances endothelial nitric oxide synthesis in streptozotocin-induced diabetic rats

This study tested the hypothesis that dietary arginine supplementation increases endothelial tetrahydrobiopterin (BH(4)) availability for nitric oxide (NO) synthesis in diabetic rats. Streptozotocin-induced diabetic rats either were given unrestricted access to a casein-based diet (Expt. 1) or were pair-fed the diet on the basis of the food intake per kg of body weight of nondiabetic rats (Expt. 2). Beginning 1 d after vehicle or streptozotocin injection, arginine-HCl (1.51%) or alanine (isonitrogenous control, 2.55%) was added daily to the drinking water for nondiabetic rats, whereas concentrations were adjusted (0.43% arginine-HCl and 0.73% alanine) in the drinking water for diabetic rats (which consumed more water) to ensure isonitrogenous provision. At 2 wk after the initiation of arginine supplementation, coronary endothelial cells and plasma were obtained for the measurement of NO synthesis and metabolites. In both experiments, plasma and endothelial concentrations of N(G)-monomethylarginine, asymmetric dimethylarginine, and symmetric dimethylarginine increased, but those of arginine as well as endothelial BH(4) availability and NO synthesis decreased in diabetic rats, compared with nondiabetic rats. In both diabetic and nondiabetic rats, arginine supplementation increased plasma concentrations of arginine and insulin, endothelial concentrations of arginine and BH(4), and endothelial NO synthesis, but did not affect plasma and endothelial concentrations of methylarginines or plasma concentrations of homocysteine. Dietary arginine supplementation or provision of a BH(4) precursor normalized endothelial NO synthesis in diabetic rats. Arginine supplementation did not affect plasma glucose levels in nondiabetic rats, but reduced body weight loss and plasma glucose levels in diabetic rats. Thus, dietary L-arginine supplementation stimulates endothelial NO synthesis by increasing BH(4) provision, which is beneficial for vascular function and glucose homeostasis in diabetic subjects.