Folic Acid Does Not Improve Endothelial Function in Obese Children and Adolescents

Abstract

OBJECTIVE -Obese children have severe endothelial dysfunction as measured by flowmediated 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 Ϯ SD age 13.3 Ϯ 2.2 years, and BMI Z score 2.29 Ϯ 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 Ϯ 5.03 and 6.56 Ϯ 4.79%, respectively, vs. placebo group: 5.17 Ϯ 3.54 and 5.79 Ϯ 4.26%, respectively; P ϭ 0.6). Folate supplementation increased serum folate and RCF by 18.4 nmol/l (P Ͻ 0.001) and 240.1 nmol/l (P Ͻ 0.001), respectively, and decreased tHcy by 0.95 mol/l (P ϭ 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. Diabetes Care 30:2122-2127, 2007E ndothelium is a key regulator of vascular function. Endothelial dysfunction is an early and fundamental event in the development of atherosclerosis (1). Abnormal endothelial function can be measured by ultrasound, assessing artery responses to an increase in flowmediated dilatation (FMD) and to glyceryl trinitrate-induced dilatation (GTN).Abnormal FMD correlates with abnormal coronary angiography in adults (2).Childhood obesity is an independent risk factor for adult obesity and is associated with atherosclerosis independent of adult weight (3). Obese children have severe endothelial dysfunction (4,5). We have shown that endothelial dysfunction in obese children is comparable in severity with that in children with type 1 diabetes (5). Interventions that begin early in life to improve endothelial function in obese children, in addition to metabolic and weight control, may potentially prevent atherosclerosis.BMI, waist circumference, dyslipidemia, insulin resistance, and markers of the proinflammatory state such as highsensitivity C-reactive protein (hsCRP) and increased total plasma homocyst(e)ine (tHcy) contribute to endothelial dysfunction in obesity (4,5).Folic acid improves endothelial function in adults and children with upperquartile tHcy (6 -8) and improves endothelial dysfunction in adults independently of lowering homo...

A NOS3 Polymorphism Determines Endothelial Response to Folate in Children with Type 1 Diabetes or Obesity

“…Subjects had all participated in our previous studies of endothelial function in children with diabetes or obesity, conducted prior to mandatory folate fortification in Australia, including a cross-sectional study with age/sex-matched controls 9 and 3 separate randomized double-blind placebo-controlled intervention trials assessing the effect of folate on endothelial function. [22][23][24] All studies had the same senior investigators, the same dose of folate (5 mg/d), the same outcome measures measured at baseline and 8 weeks, the same inclusion (other than diabetes 22,23 or obesity 24 ) and exclusion criteria, the same vascular function protocols, and the same ultrasound equipment and sonographer expertise. Exclusion criteria in all 4 studies were history of smoking, lipid lowering treatment, vitamin B12 deficiency, current or recent use of folate supplements, and subjects with syndromal or endocrinological causes of obesity.…”

“…This analysis, therefore, included 24 subjects from the cross-over study of folate supplementation in type 1 diabetes, 22 61 subjects who received folate in the parallel-arm study in type 1 diabetes 23 [31 received folate and placebo, 30 received folate and vitamin B6 (100 mg/d), subjects in these groups were combined as there was no difference in endothelial function at 8 weeks between them], and 28 subjects who received folate in the parallel arm study in obesity. 24 Thirty-one subjects who received vitamin B6 alone (and demonstrated an endothelial response) in the parallel arm study 23 acted as a treatment control group.…”

“…At each assessment, vascular function [FMD and glyceryl trinitrate (GTN)-mediated dilatation], serum folate, RCF, total plasma homocyst(e)ine (tHcy), vitamin B12, fasting lipids, height, weight, and blood pressure were measured as previously described. 8,9,[22][23][24] Ultrasound Assessment of Vascular Function In all studies, FMD and GTN-mediated dilatation were assessed by the same experienced sonographers using identical equipment after overnight fasting in a quiet and stable temperature environment, as previously described. 8,9,[22][23][24] In brief, brachial artery diameter was measured in longitudinal section with a 10 MHz linear array transducer using HDI 3000 ultrasound system, with a simultaneous electrocardiogram.…”

“…8,9,[22][23][24] Ultrasound Assessment of Vascular Function In all studies, FMD and GTN-mediated dilatation were assessed by the same experienced sonographers using identical equipment after overnight fasting in a quiet and stable temperature environment, as previously described. 8,9,[22][23][24] In brief, brachial artery diameter was measured in longitudinal section with a 10 MHz linear array transducer using HDI 3000 ultrasound system, with a simultaneous electrocardiogram. Each study included 4 scans: (1) resting scan; (2) reactive hyperemia scan (FMD) recorded between 45 and 75 seconds after deflation of a sphygmomanometer cuff which occluded arterial blood flow for 4 minutes; (3) recontrol scan 10-15 minutes later; and (4) post-GTN scan, 4 minutes after the sublingual administration of 400 mg GTN.…”

“…21 We have previously shown that endothelial dysfunction in children with type 1 diabetes relates to red cell folate (RCF), 8 and in intervention studies folate improves 22 or normalizes 23 endothelial function in children with type 1 diabetes, but not with obesity. 24 However, there are no studies assessing the interaction between endothelial response to folate and NOS3 polymorphisms, which may explain individual variations in response.…”