Vascular Function and Distribution of Adiponectin Isomers during Puberty in Children and Adolescents with Obesity.

INTRODUCTION: Youth with obesity have abnormal vascular function that relates to the anti-atherogenic adipose-derived hormone, adiponectin. The distribution of adiponectin isomers changes during normal puberty, but there are no data in relation to vascular function. We aimed to evaluate vascular function, adiponectin, and its isomers longitudinally in peri-pubertal youth with obesity and controls. METHODS: The study is a cohort longitudinal study involving 30 children and adolescents with obesity (body mass index [BMI] z-score 2.31 ± 0.24; age 12.8 ± 3 years, 17 male participants) and 28 age-/sex-matched healthy controls (12.8 ± 3 years, 14 male participants). Vascular function (flow-mediated dilatation [FMD], glyceryl trinitrate-mediated dilatation [GTN]), total adiponectin and isomers, and laboratory and clinical variables were assessed at 0, 18, and 36 months. RESULTS: FMD and GTN were stable during puberty in both groups, remaining consistently lower in obese children (p = 0.02, p < 0.001). The change in total (p = 0.02) and high-molecular weight (HMW) (p = 0.02) adiponectin differed between the groups: falling in controls by the end of puberty but not falling further during puberty in obesity. In obesity, impaired GTN was associated longitudinally with lower total (B = 7.85, p = 0.006) and HMW (B = 3.72, p = 0.03) adiponectin. In controls, more favourable GTN was longitudinally associated with a lower BMI z-score (B = -3.04, p = 0.027) and lower waist circumference (B = -0.35, p = 0.009). CONCLUSIONS: Vascular dysfunction and lower levels of adiponectin are associated in children and adolescents with obesity during puberty and do not deteriorate further. Healthy children's better vascular function, within the normal range, is associated with a lower BMI z-score and waist circumference.

Lack of evidence for progression of atherosclerosis during puberty in type 1 diabetes.

OBJECTIVES: Children with type 1 diabetes have early changes in vascular structure with increased aortic intima-media thickness (aIMT) or carotid IMT (cIMT). aIMT may be an earlier, more sensitive marker; however, longitudinal data in type 1 diabetes are lacking. This study will aim to evaluate changes in vascular structure (aIMT and cIMT) over 2 yr during puberty in children with type 1 diabetes and compare them with those in healthy children. RESEARCH DESIGN AND METHODS: A total of 110 children (aged 10-18 yr, 55 males) participated in a prospective cohort study, including 77 children with type 1 diabetes and 33 age- and sex-matched healthy children. Ultrasound assessments of aIMT and cIMT; and clinical and biochemical data were collected at baseline and 2 yr later. RESULTS: Mean and maximal aIMT or cIMT did not worsen over time in children with type 1 diabetes compared with healthy children. Longer duration of diabetes related to an increase in aIMT. Improvement in HDL cholesterol and leptin related to a decrease in aIMT. Higher baseline IMT related to an improvement in IMT in children with type 1 diabetes (mean and maximal aIMT: ß = -0.52, p < 0.001; ß = -0.49, p = 0.001, and mean and maximal cIMT: ß = -0.36, p = 0.003; ß = -0.40, p = 0.001), independent of cardiovascular risk factors. CONCLUSIONS: Aortic and carotid IMT does not deteriorate during puberty in children with type 1 diabetes. This has implications for the design of interventional studies in this important age group.

Adolescents with congenital adrenal hyperplasia because of 21-hydroxylase deficiency have vascular dysfunction.

CONTEXT: Patients with congenital adrenal hyperplasia (CAH) because of 21-hydroxylase deficiency have multiple vascular risk factors. Young adults with CAH have increased intima media thickness, but there have been no studies of vascular function and structure in children with CAH. OBJECTIVE: To establish whether children with CAH have reduced vascular function and increased carotid intima media thickness (cIMT) when compared to healthy and obese children. DESIGN AND PATIENTS: Cross-sectional study of 14 patients (14.8 years ± 3.2, seven boys) with CAH secondary to 21-hydroxylase deficiency compared to 28 obese and 53 healthy controls. MEASUREMENTS: All subjects had assessment of endothelial function flow-mediated dilatation, (FMD), smooth muscle function glyceryl tri-nitrate dilatation (GTN) and cIMT. Anthropometric data, resting blood pressure and biochemical variables were also measured. RESULTS: Congenital adrenal hyperplasia subjects had significantly reduced FMD (4.5 ± 3.0% vs 7.5 ± 5.2%; P = 0.04) and GTN (17.2 ± 1.6% vs 28.4 ± 8.4%; P < 0.001) when compared to controls and the impairment was comparable to the obese cohort. There was no significant difference in cIMT between groups. CAH subjects had increased homoeostasis model of assessment-insulin resistance [HOMA-IR 2.5 (0.2-2.9) vs 1.8 (0.5-4.2); P = 0.04], waist-to-height ratio (0.47 ± 0.05 vs 0.44 ± 0.04; P = 0.02) and higher systolic blood pressure Z score (0.29 ± 0.9 vs-0.24 ± 0.64, P = 0.01) compared to healthy controls but not when compared to obese controls. CONCLUSIONS: Subjects with CAH have evidence of vascular dysfunction by adolescence.

Aortic intima media thickness is an early marker of atherosclerosis in children with type 1 diabetes mellitus.

OBJECTIVE: To compare aortic intima media thickness (aIMT) to carotid intima media thickness (cIMT) as a marker of early atherosclerosis in children with type 1 diabetes mellitus and to examine the associations of aIMT to known cardiovascular risk factors. STUDY DESIGN: 66 children with type 1 diabetes mellitus (age, 14.1 +/- 2.5 years; 37 male) and 32 healthy control subjects (age, 14.2 +/- 3 years; 15 male) underwent assessment of vascular structure (cIMT and aIMT) and vascular function (flow mediated dilatation [FMD] and glyceryl trinitrate induced dilatation [GTN]). Fasting blood tests were taken to measure levels of hemoglobin A1c, high sensitive C reactive protein, total homocyst(e)ine, serum folate, red cell folate, and lipids. RESULTS: aIMT, but not cIMT, was significantly greater in the children with type 1 diabetes mellitus than in control subjects (P < .001). In children with type 1 diabetes mellitus, aIMT correlated with glycosylated hemoglobin (r = 0.31, P = .01) and was independently associated with age (beta = 0.38, P = .001) and low-density lipoprotein cholesterol level (beta = 0.38, P = .001). Vascular function (GTN) was worse in children with type 1 diabetes mellitus who had an aIMT >95th percentile, as defined with the control subjects. CONCLUSIONS: aIMT is an earlier marker than cIMT of preclinical atherosclerosis in children with type 1 diabetes mellitus and relates to known cardiovascular risk factors and metabolic control.

Adiponectin relates to smooth muscle function and folate in obese children.

OBJECTIVE: Adiponectin, an adipocyte-specific protein, stimulates nitric oxide production and may mediate associations between visceral obesity and vascular dysfunction. Adiponectin is lower in obese children but its relationship with vascular function has not been clarified in childhood. We aimed to evaluate the association between adiponectin and vascular function in obese and healthy children. METHODS: Forty-nine obese and thirty-three non-obese children (aged 13.4+/-2.8 years, 37 males) participated in a cross-sectional study. We measured adiponectin, vascular endothelial and smooth muscle function (Flow mediated dilatation [FMD] and glyceryl trinitrate induced dilatation [GTN]), serum folate, red cell folate (RCF), homocysteine, lipids, glucose and insulin. Because adiponectin related to RCF we examined the effect of folate supplementation on adiponectin levels in obese children in a previously conducted randomized folate intervention trial. This included two assessments prior to intervention and two post intervention. RESULTS: Adiponectin, FMD and GTN were lower in obese compared with non-obese children (p = 0.002, p = 0.03 and p < 0.001, respectively). In obesity, adiponectin related to GTN (beta = 0.46, p < 0.001), RCF (beta = 0.4, p = 0.001) and LDL cholesterol (beta = 0.33, p = 0.004). Adiponectin associations were affected by gender and adiponectin related to female gender (B = 0.22, p = 0.03). During the intervention trial, folic acid did not improve adiponectin levels (p = 0.8) in spite of increasing serum folate and RCF (p < 0.001, p < 0.001, respectively) and decreasing homocysteine levels (p = 0.008). CONCLUSIONS: Obese children have lower adiponectin, which relates to decreased smooth muscle function and lower folate status. Despite adiponectin relating to folate status, folic acid supplementation does not improve adiponectin in obese children.

Hs-CRP is associated with weight, BMI, and female sex but not with endothelial function in children with type 1 diabetes.

BACKGROUND: Atherosclerosis is an inflammatory process, and high-sensitivity C-reactive protein (Hs-CRP), a marker of inflammation, predicts cardiovascular events in adults. Vascular endothelial and smooth muscle dysfunction, measurable precursors of atherosclerosis, begin in childhood. Therefore, we sought to determine if Hs-CRP is associated with vascular endothelial and smooth muscle dysfunction in children with type 1 diabetes mellitus (T1DM) and healthy control subjects. METHODS: Hs-CRP and endothelial function assessed by flow-mediated dilatation (FMD) and smooth muscle function assessed by glyceryl-trinitrate (GTN)-induced dilatation were measured in 121 subjects with T1DM aged 14.1 (2.9) yr, of whom 31 were also studied at 4 and 8 wk, and in 33 healthy controls aged 14.2 (3.6) yr. RESULTS: Hs-CRP did not differ between subjects with T1DM and healthy, age-matched controls. In both controls and subjects with T1DM, Hs-CRP did not relate to FMD or GTN at baseline or at intervals over 8 wk in T1DM. Hs-CRP did not change over time. In T1DM, but not healthy controls, Hs-CRP related to body mass index (BMI) z-score (r = 0.47, p < 0.001), weight z-score (r = 0.41, p < 0.001), and female sex (p = 0.008). CONCLUSIONS: Hs-CRP is not associated with early vascular dysfunction in children with T1DM. However, in children and adolescents with T1DM, Hs-CRP was associated with female sex and children with higher BMI, suggesting that these groups may be at greater cardiovascular risk. Maintenance of a healthy BMI may be important in the prevention of vascular disease of T1DM.

Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes.

OBJECTIVE: In a prospective birth cohort study, we followed infants who had a first-degree relative with type 1 diabetes to investigate the relationship between early growth and infant feeding and the risk of islet autoimmunity. RESEARCH DESIGN AND METHODS: Infants with a first-degree relative with type 1 diabetes were identified during their mother's pregnancy. Dietary intake was recorded prospectively to determine duration of breast-feeding and age at introduction of cow's milk protein, cereals, meat, fruit, and vegetables. At 6-month reviews, length (or height) and weight, antibodies to insulin, GAD65, the tyrosine phosphatase-like insulinoma antigen, and tissue transglutaminase were measured. Islet autoimmunity was defined as persistent elevation of one or more islet antibodies at consecutive 6-month intervals, including the most recent measure, and was the primary outcome measure. RESULTS: Follow-up of 548 subjects for 5.7 +/- 3.2 years identified 46 children with islet autoimmunity. Weight z score and BMI z score were continuous predictors of risk of islet autoimmunity (adjusted hazard ratios 1.43 [95% CI 1.10-1.84], P = 0.007, and 1.29 [1.01-1.67], P = 0.04, respectively). The risk of islet autoimmunity was greater in subjects with weight z score >0 than in those with weight z score < or =0 over time (2.61 [1.26-5.44], P = 0.01). Weight z score and BMI z score at 2 years and change in weight z score between birth and 2 years, but not dietary intake, also predicted risk of islet autoimmunity. CONCLUSIONS: Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes.

Folic acid does not improve endothelial function in obese children and adolescents.

OBJECTIVE: Obese children have severe endothelial dysfunction as measured by flow-mediated dilation (FMD). We have shown that folic acid normalizes endothelial function in children with type 1 diabetes who have a similar degree of endothelial dysfunction but lower total plasma homocyst(e)ine (tHcy) and higher folate status. Our aim was to evaluate, for the first time, the effect of folate supplementation on endothelial dysfunction in obese children. RESEARCH DESIGN AND METHODS: A total of 53 obese subjects (26 male, mean +/- SD age 13.3 +/- 2.2 years, and BMI Z score 2.29 +/- 0.25) participated in a randomized, double-blind, placebo-controlled, parallel trial of oral folic acid (5 mg/day) or placebo for 8 weeks. Before and after the intervention, we assessed endothelial function (FMD), smooth muscle function (glyceryl trinitrate-induced dilatation [GTN]), high-sensitivity C-reactive protein (hsCRP), tHcy, serum folate, red cell folate (RCF), and lipids. RESULTS: There were no group differences at baseline. FMD did not change with the intervention (folic acid group pre- and postintervention: 6.42 +/- 5.03 and 6.56 +/- 4.79%, respectively, vs. placebo group: 5.17 +/- 3.54 and 5.79 +/- 4.26%, respectively; P = 0.6). Folate supplementation increased serum folate and RCF by 18.4 nmol/l (P < 0.001) and 240.1 nmol/l (P < 0.001), respectively, and decreased tHcy by 0.95 microl (P = 0.008). The intervention did not change GTN, hsCRP, or lipids. CONCLUSIONS: Folic acid supplementation does not improve endothelial function in obese children without diabetes despite increasing folate status and reducing tHcy. This is in contrast to the response to folate in children with type 1 diabetes.

Vascular endothelial and smooth muscle function relates to body mass index and glucose in obese and nonobese children.

CONTEXT: Endothelial and smooth muscle dysfunction are critical precursors of atherosclerosis. These can be detected in children at risk of cardiovascular disease. OBJECTIVE: The objective of this study is to evaluate endothelial and smooth muscle function and their determinants using flow-mediated dilatation (FMD) and glyceryl trinitrate-mediated dilatation (GTN) in obese, nonobese, and type 1 diabetes mellitus (T1DM) children. DESIGN: This is a cross-sectional study. SUBJECTS: The study subjects were 270 children [140 males, mean age 13.7 (2.8) yr] including 58 obese, 53 nonobese, and 159 T1DM children. MEASUREMENTS: Vascular function (FMD and GTN), body mass index (BMI) z-score, blood pressure, glucose, glycosylated hemoglobin, lipids, folate, homocysteine, and high sensitive C-reactive protein were measured. RESULTS: FMD and GTN were significantly lower in obese and T1DM compared with nonobese subjects (P < 0.001, P < 0.001). FMD and GTN were similarly reduced in obese and T1DM subjects (P = 0.22, P = 0.28). In all nondiabetic subjects (n = 111), both FMD and GTN were significantly and independently related to BMI z-score (r = -0.28, P = 0.003, beta = -0.36, P < 0.001) and weight z-score (beta = -0.31, P = 0.002; r = -0.52, P < 0.001). FMD related independently to total cholesterol (beta = -0.22, P = 0.02). GTN related independently to vessel diameter (beta = -0.49, P < 0.001). GTN related to glucose within the normal range (r = -0.34, P = 0.001). CONCLUSIONS: Children with obesity and T1DM have a similar degree of vascular dysfunction. BMI and weight adjusted for age and sex relate to endothelial and smooth muscle function in nonobese and obese children. Glucose relates to smooth muscle function in nonobese nondiabetic children. This suggests a continuum effect of BMI and glucose within the normal range on vascular function in childhood.

Folate and vitamin B6 rapidly normalize endothelial dysfunction in children with type 1 diabetes mellitus.

BACKGROUND: Endothelial dysfunction, a precursor of vascular disease, begins early in type 1 diabetes mellitus and is associated with folate status. METHODS: A randomized, double-blind, placebo-controlled study of folate (5 mg daily) and vitamin B6 (100 mg daily) in 124 children with type 1 diabetes determined the immediate and 8-week effects of these vitamins, alone and in combination, on endothelial function. Endothelial function, assessed as flow-mediated dilation and glyceryltrinitrate-induced dilation with high-resolution ultrasound of the brachial artery, was measured at baseline, at 2 and 4 hours after the first dose (n = 35), and at 4 and 8 weeks of treatment (n = 122). RESULTS: Flow-mediated dilation normalized in all treatment groups. From baseline to 8 weeks, flow-mediated dilation improved with folate from 2.6% +/- 4.3% (mean +/- SD) to 9.7% +/- 6.0%, with vitamin B6 from 3.5% +/- 4.0% to 8.3% +/- 4.2%, and with folate/vitamin B6 from 2.8% +/- 3.5% to 10.5% +/- 4.4%. This improvement in flow-mediated dilation occurred within 2 hours and was maintained at 8 weeks for each treatment. Flow-mediated dilation in the placebo group, and glyceryltrinitrate-induced dilation in all groups, did not change. Increases in serum folate, red cell folate, and serum vitamin B6 levels related to increases in flow-mediated dilation. Improvement in flow-mediated dilation was independent of changes in total plasma homocyst(e)ine, glucose, hemoglobin A1c, and high-sensitivity C-reactive protein levels. Baseline red cell folate levels and baseline diastolic blood pressure were related inversely to improvement in flow-mediated dilation. Serum triglyceride and low-density lipoprotein cholesterol inversely related to baseline flow-mediated dilation. CONCLUSIONS: High-dose folate and vitamin B6 normalized endothelial dysfunction in children with type 1 diabetes. This effect was maintained over 8 weeks, with no additional benefit from combination treatment.

Characterization of a C57BL/6 congenic mouse strain of mucopolysaccharidosis type IIIA.

The original mucopolysaccharidosis type IIIA (MPS IIIA) mice were identified in a mixed background with contributions from four different strains. To ensure long-term stability and genetic homogeneity of this lysosomal storage disease (LSD) model, the aim of this study was to develop and characterize a C57BL/6 congenic strain. The B6.Cg-Sgsh(mps3a) strain compares favorably with the original mixed donor strain, exhibiting low liver sulfamidase activity and significant brain heparan sulfate-derived disaccharide elevation from birth. A rapid increase in brain disaccharide levels occurred after birth, with a plateau reached by 13 weeks of age at 110x the levels observed in brains of age-matched unaffected mice. Typical lysosomal inclusions were observed in cerebral cortical and cerebellar neurons and in liver hepatocytes and Kupffer cells. Ubiquitin-positive spheroids and GM(2)-ganglioside were also detected in brain. Using the Morris water maze in male mice, impaired memory and spatial learning was evident at 20 weeks of age in B6.Cg-Sgsh(mps3a) MPS IIIA mice. Other behavioral changes include motor, cognitive and sensory deficits, and aggression. Male B6.Cg-Sgsh(mps3a) MPS IIIA mice exhibited more behavioral abnormalities than B6.Cg-Sgsh(mps3a) MPS IIIA females, as observed previously in the original mixed background strain. Affected mice generally survive to 9 to 12 months of age, before death or euthanasia for humane reasons. Overall, minor differences were apparent between the new congenic and previously described mixed MPS IIIA strains. Availability of an in-bred strain will ensure more reproducible experimental outcomes thereby assisting in our goal of developing effective therapies for LSD with central nervous system disease.

Longitudinal study of normal hip development by ultrasound.

In the management of a newborn's hips, ultrasonography has proven to be useful. The progression of measurements at different ages in normal hips has not been thoroughly investigated. The purpose of this prospective study was to assess the longitudinal development of clinically stable hips. Forty newborns (80 hips) were assessed by ultrasonography at birth and at 6 and 12 weeks of age. Femoral head coverage (FHC), alpha angles, and beta angles were measured. The results showed a significant change in values between the three points in time for all measurements (P < 0.001). The mean FHC progressed from 58.4% to 65.6% to 69.3%, the mean alpha angle from 70.2 degrees to 76.8 degrees to 80.3 degrees , and the mean beta angle from 52.1 degrees to 45.7 degrees to 42.9 degrees . In clinically stable hips, the FHC and alpha and beta angles change significantly over time; therefore, it is important to consider the child's age when interpreting ultrasound images.

Folic acid improves endothelial function in children and adolescents with type 1 diabetes.

OBJECTIVE: To evaluate the effect of folate supplementation on endothelial function in children and adolescents with type 1 diabetes. STUDY DESIGN: Thirty-six subjects with type 1 diabetes age 13.6+/-2.6 years completed a randomized, double-blind, placebo-controlled crossover trial. Each subject received 8 weeks of oral folic acid (5 mg/d) and 8 weeks of placebo, with an 8-week washout period. Before and after each intervention, we assessed endothelial function by using brachial artery responses to flow (flow-mediated dilatation [FMD]) and glyceryl trinitrate, von Willebrand factor, glucose, hemoglobin A1c, total plasma homocyst(e)ine (tHcy), vitamin B(12), serum folate, and red cell folate (RCF). RESULTS: Folic acid increased FMD by 2.58 (3.1-5.7) % (95% confidence interval, 1.28-3.88), whereas placebo did not change FMD (-0.42%; 95% confidence interval, -1.67 to 0.83; P<.001). Folic acid increased serum folate by 14 nmol/L (6.2 ng/mL, P<.001) and RCF by 467.2 nmol/L (206 ng/mL, P<.001). Change in FMD was related to change in serum folate (r=0.46, P=.005) and RCF (r=0.39, P=.02). Glyceryl trinitrate responses, von Willebrand factor, tHcy, and hemoglobin A1c were not affected by the intervention. CONCLUSIONS: Short-term high-dose folic acid improves endothelial function in children and adolescents with type 1 diabetes and normal folate status independently of tHcy.

Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux.

OBJECTIVE: To assess the efficacy of omeprazole in treating irritable infants with gastroesophageal reflux and/or esophagitis. STUDY DESIGN: Irritable infants (n=30) 3 to 12 months of age met the entry criteria of esophageal acid exposure >5% (n=22) and/or abnormal esophageal histology (n=15). They completed a 4-week, randomized, double-blind, placebo-controlled crossover trial of omeprazole. Cry/fuss diary (minutes/24 hours) and a visual analogue scale of infant irritability as judged by parental impression were obtained at baseline and the end of each 2-week treatment period. RESULTS: The reflux index fell significantly during omeprazole treatment compared with placebo (-8.9%+/-5.6%, -1.9%+/-2.0%, P<.001). Cry/fuss time decreased from baseline (267+/-119), regardless of treatment sequence (period 1, 203+/-99, P<.04; period 2, 188+/-121, P<.008). Visual analogue score decreased from baseline to period 2 (6.8+/-1.6, 4.8+/-2.9, P=.008). There was no significant difference for both outcome measures while taking either omeprazole or placebo. CONCLUSIONS: Compared with placebo, omeprazole significantly reduced esophageal acid exposure but not irritability. Irritability improved with time, regardless of treatment.

Dietary fats do not contribute to hyperlipidemia in children and adolescents with type 1 diabetes.

OBJECTIVE: To determine the relative influence of diet, metabolic control, and familial factors on lipids in children with type 1 diabetes and control subjects. RESEARCH DESIGN AND METHODS: We assessed fasting serum cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, lipoprotein(a), apolipoprotein (apo)-A1, and apoB in 79 children and adolescents with type 1 diabetes and 61 age- and sex-matched control subjects, together with dietary intakes using a quantitative food frequency questionnaire. RESULTS: Total cholesterol, LDL cholesterol, apoB, HDL cholesterol, and apoA1 were significantly higher in children with diabetes. Children with diabetes had higher percentage energy intake from complex carbohydrates (P = 0.001) and fiber intake (P = 0.02), and they had lower intake of refined sugar (P < 0.001) and percentage energy from saturated fat (P = 0.045) than control subjects. Total cholesterol (beta = 0.43, P < 0.001), LDL cholesterol (beta = 0.4, P < 0.001), and apoB (beta = 0.32, P = 0.006) correlated independently with HbA(1c) but not dietary intake. HDL cholesterol (beta = 0.24, P = 0.05) and apoA1 (beta = 0.32, P = 0.004) correlated independently with HbA(1c), and HDL cholesterol (beta = -0.34, P = 0.009) correlated with percentage energy intake from complex carbohydrates. Triglycerides correlated independently with percentage energy intake from complex carbohydrates (beta = 0.33, P = 0.01) and insulin dose (beta = 0.26, P = 0.04). Subjects with diabetes and elevated LDL (>3.35 mmol/l, >130 mg/dl), for whom dietary therapy would be recommended, had significantly higher HbA(1c) (P = 0.007), but they had higher intake of complex carbohydrates than subjects with LDL cholesterol <3.35 mmol/l. CONCLUSIONS: Lipid abnormalities remain common in children and adolescents with type 1 diabetes who adhere to current dietary recommendations, and they relate to metabolic control but not dietary intake.

Endothelial dysfunction relates to folate status in children and adolescents with type 1 diabetes.

Endothelial dysfunction occurs early in the development of vascular disease in diabetes. Total plasma homocyst(e)ine (tHcy) is associated with endothelial dysfunction. We therefore aimed to assess endothelial function in children with type 1 diabetes in relation to tHcy and its determinants. Endothelial function was assessed in 36 children with type 1 diabetes aged 13.7 +/- 2.2 years and 20 age- and sex-matched control subjects using ultrasound assessment of flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)-dependent brachial artery responses. von Willebrand factor (vWF) and thrombomodulin, markers of endothelial activation, were measured in 64 children with type 1 diabetes and 52 control subjects. Fasting glucose, tHcy, serum and red cell folate, vitamin B12, HbA(1c), creatinine, and lipids were also measured. FMD (5.2 +/- 4.7 vs. 9.1 +/- 4.0%, P = 0.002) and the ratio of FMD:GTN-induced dilatation (0.22 +/- 0.39 vs. 0.41 +/- 0.29%, P = 0.008) were significantly lower in diabetic subjects, indicating endothelial dysfunction. In diabetic subjects, red cell folate correlated independently with FMD (beta = 0.42, P = 0.028) and the ratio of FMD:GTN-induced dilatation (beta = 0.59, P < 0.001). Resting vessel diameter correlated independently with tHcy (beta = -0.51, P < 0.001) and height (beta = 0.65, P < 0.001). vWF correlated independently with HbA(1c) (beta = 0.38, P = 0.003), and thrombomodulin correlated independently with red cell folate (beta = -0.38, P = 0.005), tHcy (beta = -0.37, P = 0.004), diastolic blood pressure (beta = -0.28, P = 0.025), and creatinine clearance (beta = 0.26, P = 0.033). Children with type 1 diabetes have early endothelial dysfunction. Better folate status is associated with better endothelial function, as measured by higher FMD, higher FMD:GTN ratio, and lower thrombomodulin. Folate may therefore protect against endothelial dysfunction in children with diabetes.