Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate

Etten, Ronald W van; Koning, Eelco J.P. de; Verhaar, Marianne C.; Gaillard, Carlo A. J. M.; Rabelink, Ton J.

doi:10.1007/s00125-002-0862-1

Cited by 125 publications

(85 citation statements)

References 47 publications

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“…In our study, endothelial function in obese children did not improve despite a significant decrease in tHcy. However, direct benefits of folate within 2-4 h on endothelial function, independent of homocysteine lowering, are reported in vitro (13)(14)(15)(16) and in type 1 and type 2 diabetes in our studies and others' (10, 17,18,24,25). Consistent with these findings is the evidence that low RCF independent of homocysteine in adults is associated with increased intima-media thickness (26).…”

Section: Statisticssupporting

confidence: 90%

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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Section: Statisticssupporting

confidence: 90%

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

et al. 2007

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“…[7][8][9][10] However, when we started our study, there was limited information in subjects with diabetes mellitus. Using forearm plethysmography, van Etten et al 17 demonstrated that subjects with type 2 diabetes have impaired endothelium-dependent, serotonin-induced vasodilation and mildly reduced endotheliumindependent vasodilation in response to sodium nitroprusside. Acute intra-arterial administration of 5-methyltetrahydrofolate, the active metabolite of folic acid, restored the endothelium-dependent vasodilation, but had no effect on endothelium-independent vasodilation in these subjects.…”

Section: Discussionmentioning

confidence: 99%

Folic acid improves endothelial dysfunction in type 2 diabetes - an effect independent of homocysteine-lowering

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Giddens

et al. 2006

Vasc Med

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Diabetes is associated with endothelial dysfunction, which in part may be related to uncoupling of the endothelial nitric oxide (NO) synthase enzyme, thus reducing the availability of NO. As folates may potentially reverse the uncoupling of NO synthase, we wanted to determine whether folic acid supplementation could modulate endothelial function and markers of inflammation in patients with type 2 diabetes without vascular disease. Nineteen patients with type 2 diabetes were treated with folic acid (10 mg/day for 2 weeks) versus placebo in a randomized, placebo-controlled, cross-over study with an 8-week washout period between treatments. Fasting endothelium-dependent flow-mediated dilatation (FMD) of the brachial artery, endothelium-independent nitroglycerin-mediated dilatation (NMD), plasma homocysteine, serum lipids, folate, and inflammatory markers (high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, interleukin-18, tumor necrosis factor-alpha) were assessed after each 2-week treatment period. Folic acid supplementation significantly increased folate levels and lowered plasma homocysteine levels. Folic acid significantly improved FMD compared to placebo (5.8 Ϯ 4.8% vs 3.2 Ϯ 2.7%, p ϭ 0.02). There were no significant effects of folic acid supplementation on lipids, NMD, or the inflammatory markers. There was no relationship between the change in homocysteine and the improvement in FMD. Thus, 2 weeks of folic acid supplementation can improve endothelial dysfunction in type 2 diabetics independent of homocysteinelowering, but does not modulate markers of inflammation.

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“…Several reports have shown that both endothelium-dependent and -independent vasodilation are impaired in this disease (1)(2)(3)(4)(5)(6). This reduction in vascular reactivity has been attributed to decreased endothelial nitric oxide (NO) synthesis (3,4), increased NO degradation (2,6), and/or abnormalities in vascular smooth muscle (3).…”

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confidence: 99%

Reduced Expression of Gi in Erythrocytes of Humans With Type 2 Diabetes Is Associated With Impairment of Both cAMP Generation and ATP Release

et al. 2006

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Human erythrocytes, by virtue of their ability to release ATP in response to physiological stimuli, have been proposed to participate in the regulation of local blood flow. A signal transduction pathway that relates these stimuli to ATP release has been described and includes the heterotrimeric G protein G i and adenylyl cyclase (AC). In this cell, G i activation results in increases in cAMP and, ultimately, ATP release. It has been reported that G i expression is decreased in animal models of diabetes and in platelets of humans with type 2 diabetes. Here, we report that G i2 expression is selectively decreased in erythrocytes of humans with type 2 diabetes and that this defect is associated with reductions in cAMP accumulation and ATP release in response to incubation of erythrocytes with mastoparan 7 (10 mol/l), an activator of G i . Importantly, this defect in ATP release correlates inversely with the adequacy of glycemic control as determined by levels of HbA 1c (A1C). These results demonstrate that in erythrocytes of humans with type 2 diabetes, both G i expression and ATP release in response to mastoparan 7 are impaired, which is consistent with the hypothesis that this defect in erythrocyte physiology could contribute to the vascular disease associated with this clinical condition. Diabetes 55: 3588 -3593, 2006

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Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate

Cited by 125 publications

References 47 publications

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

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

Folic acid improves endothelial dysfunction in type 2 diabetes - an effect independent of homocysteine-lowering

Reduced Expression of Gi in Erythrocytes of Humans With Type 2 Diabetes Is Associated With Impairment of Both cAMP Generation and ATP Release

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