Endothelial Dysfunction Relates to Folate Status in Children and Adolescents With Type 1 Diabetes

Wiltshire, Esko; Gent, Roger; Hirte, Craig; Peña, Alexia S; Thomas, David W.; Couper, Jennifer

doi:10.2337/diabetes.51.7.2282

Cited by 92 publications

(104 citation statements)

References 27 publications

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“…Indeed, these findings suggest that there is normal vascular smooth muscle function in diabetic subjects and that defective endothelial cell acetylcholine receptor excitation (31) and a reduction in NO production (32) are seen relatively early in type 1 diabetes. Abnormalities in the endothelium/NO pathway have been reported in young adults with type 1 diabetes who have no clinical evidence of vascular disease, and these complications develop early (9,30,33). In diabetes, prolonged hyperglycemia is a primary cause of most long-term complications.…”

Section: Discussionmentioning

confidence: 99%

Impaired Pressure-Induced Vasodilation at the Foot in Young Adults With Type 1 Diabetes

et al. 2004

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Vascular and neurological mechanisms are both likely to be involved in foot ulcer. We recently reported a pressure-induced vasodilation (PIV), relying on unmyelinated afferent excitation. We previously found that cutaneous blood flow in response to locally applied pressure might be impaired in diabetic patients because of the combined effects of low cutaneous temperature and alterations in microcirculatory function. Therefore, we aimed to analyze whether, at a relatively high cutaneous temperature, PIV is present in type 1 diabetes and to assess endothelial-dependent vasodilation and endothelium-independent vasodilation. We measured cutaneous blood flow using laser Doppler flowmetry on the head of the first metatarsus in response to applied pressure at 5.0 mmHg/min in warm conditions (29.5 ؎ 0.2°C). Responses to iontophoresis of acetylcholine (endothelium dependent) and sodium nitroprusside (endothelium independent) were measured using laser Doppler flowmetry in the forearm. The data indicate that PIV exists at the foot level in normal subjects, whereas it was not found in diabetic patients. In diabetic patients, the nonendothelial-mediated response to sodium nitroprusside was preserved, whereas the endothelial-mediated response to acetylcholine was impaired. These findings might be relevant to the high prevalence of foot ulcer that occurs in diabetic patients. Diabetes 53: [721][722][723][724][725] 2004

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Section: Discussionmentioning

confidence: 99%

Impaired Pressure-Induced Vasodilation at the Foot in Young Adults With Type 1 Diabetes

et al. 2004

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“…Reactive hyperemia was calculated as the flow in the first 15 s after cuff deflation divided by the flow during the resting scan. The coefficient of variation between 20 subjects is 3.9% for FMD and 4.0% for GTN (19).…”

Section: Vascular Function Assessmentmentioning

confidence: 94%

“…Endothelial and smooth muscle function (FMD and GTN) were assessed after overnight fasting, as previously reported (5, [17][18][19] Images were recorded onto VHS videotape and analyzed subsequently by a blinded observer. For each scan, measurements were made incident with the electrocardiogram R-wave (i.e., at end diastole) over four cardiac cycles using ultrasonic calipers.…”

Section: Vascular Function Assessmentmentioning

confidence: 99%

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

et al. 2007

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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...

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“…Adult and pediatric studies of endothelial dysfunction in diabetic patients have demonstrated significant associations with high LDL, low HDL, hypertension, glycemic control, duration of disease, folic acid status, exercise regimen, and sex (3,5,12,31). Although we did demonstrate that type 1 diabetes was associated with increased arterial stiffness, this study did not find any significant associations with lipids, blood pressure, glycemic control, cytokines, family history, or sex in the children with diabetes.…”

Section: Sexmentioning

confidence: 99%

Radial Artery Tonometry Demonstrates Arterial Stiffness in Children With Type 1 Diabetes

et al. 2004

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OBJECTIVE -To determine if children with type 1 diabetes have increased arterial stiffness by estimating augmentation index with the simple noninvasive technique of radial artery tonometry.RESEARCH DESIGN AND METHODS -We studied 98 type 1 diabetic children and 57 healthy control subjects, ages 10 -18 years, matched for age, sex, race, and BMI, generating 43 matched pairs. Radial artery tonometry was performed, and blood was collected for analysis of fasting lipids, HbA 1c , glucose, and cytokines in all children.RESULTS -Children with diabetes had a significantly higher augmentation index corrected to a heart rate of 75 (AI 75 ) than their matched control subjects. Mean AI 75 in type 1 diabetic subjects was 1.11 Ϯ 10.15 versus Ϫ3.32 Ϯ 10.36 in control subjects. The case-control difference was 5.20 Ϯ 11.02 (P ϭ 0.0031).CONCLUSIONS -Children with type 1 diabetes have increased arterial stiffness compared with healthy control subjects. Radial artery tonometry is a simple noninvasive technique that could be added to the armamentarium of tests used to provide cardiovascular risk stratification in children with type 1 diabetes. Many adult studies have demonstrated that the incidence of cardiovascular events can be lessened with reduction of plasma cholesterol and optimal management of hypertension. Unfortunately, the majority of patients who are being treated aggressively have already manifested cardiovascular complications. Because efficacy of intervention in children cannot be measured by cardiovascular event end points, surrogate markers must be used. Brachial artery reactivity is a technique that measures the endothelium-dependent dilation of the brachial artery in response to reactive hyperemia. In patients with endothelial dysfunction, the ability of the artery to dilate is impaired. Endothelial dysfunction, as measured by decreased brachial reactivity, has been shown to be an independent predictor of cardiovascular events (2). Impaired brachial reactivity has been demonstrated in adults and in a small group of children with type 1 diabetes (3,4). DiabetesRecent studies have demonstrated that endothelial function, as measured by brachial reactivity and carotid intimamedial thickness (IMT), are abnormal in children with type 1 diabetes (5); however, no one has yet demonstrated if radial tonometry can provide similar results. Because radial tonometry can be performed in nearly any clinic setting, is easy and affordable to perform, and provides the user with instant analysis of the patient's arterial stiffness, tonometry has a potential advantage over brachial reactivity and carotid IMT as a clinically useful tool.To test the utility of radial tonometry, we studied whether children with type 1 diabetes had increased arterial stiffness, as measured by augmentation index (AI), when compared with healthy control subjects. To gain further insight into their cardiovascular risk profiles, we obtained historical data on family history, exercise, and glycemic control and obtained blood for lipid, glucose, HbA 1c , and cyto...

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Endothelial Dysfunction Relates to Folate Status in Children and Adolescents With Type 1 Diabetes

Cited by 92 publications

References 27 publications

Impaired Pressure-Induced Vasodilation at the Foot in Young Adults With Type 1 Diabetes

Impaired Pressure-Induced Vasodilation at the Foot in Young Adults With Type 1 Diabetes

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

Radial Artery Tonometry Demonstrates Arterial Stiffness in Children With Type 1 Diabetes

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