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

R.W. van Etten; E. de Koning; M. Verhaar; C. Gaillard; T. Rabelink

doi:10.1007/s00125-002-0862-1

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

R.W. van Etten, E. de Koning, M. Verhaar, C. Gaillard, T. Rabelink

Research output: Contribution to journal › Article › Academic › peer-review

102 Citations (Scopus)

Abstract

Aims/hypothesis. Patients with diabetes are characterised by endothelial dysfunction and cardiovascular mortality. In particular endothelium-derived nitric oxide has emerged as a first line mechanism against atherosclerosis. Hyperglycaemia causes oxygen radical stress but has also been associated with endothelial nitric oxide synthase uncoupling, both lead to decreased nitric oxide-availability. We recently showed that folate reverses eNOS uncoupling in vitro. Therefore we hypothesise that folate improves endothelial function in Type II (non-insulin-dependent) diabetes mellitus in vivo. Methods. Using forearm plethysmography, we evaluated the effect of local, intra-arterial administration of 5-methyltetrahydrofolate (5-MTHF, the active form of folic acid, 1 μg/100 ml FAV/min) on forearm blood flow in 23 patients with Type II diabetes and 21 control subjects, matched for age, sex, blood pressure, body mass index, weight and smoking habits. Serotonin as a stimulator of nitric oxide-dependent vasodilation and sodium nitroprusside as a stimulator of endothelium-independent vasodilation were infused. Results. Serotonin-induced vasodilation was blunted (53±30 vs 102±66 M/C%, p<0.005) and nitroprusside-induced vasodilation was mildly reduced (275±146 vs 391±203 M/C%, p<0.05) in patients with Type II diabetes compared to control subjects. 5-MTHF improved nitric oxide-mediated vasodilation (from 53±30 to 88±59 M/C%, p<0.05) in patients with Type II diabetes mellitus. As expected, 5-MTHF had no effect on forearm blood flow in control subjects. Conclusion/interpretation. These data imply that folate can be used to improve nitric oxide status and to restore endothelial dysfunction in patients with Type II diabetes. Our results provide a strong rationale for the initiation of studies that investigate whether supplementation with folic acid prevents future cardiovascular events in this patient group.

Original language	English
Pages (from-to)	1004-1010
Number of pages	7
Journal	Diabetologia
Volume	45
Issue number	7
DOIs	https://doi.org/10.1007/s00125-002-0862-1
Publication status	Published - 2002

Keywords

Blood Pressure Diabetes Mellitus, Type 2/blood/*physiopathology Endothelium, Vascular/*drug effects/physiology/physiopathology Female Folic Acid/*pharmacology Heart Rate Hematinics/*pharmacology Humans Male Middle Aged Nitric Oxide/*physiology Nitroprusside/pharmacology Reference Values Serotonin/pharmacology Vasodilation/*drug effects/physiology

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10.1007/s00125-002-0862-1

https://www.ncbi.nlm.nih.gov/pubmed/12136399

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@article{cd525749c07b4952a75209c8012e1472,

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

abstract = "Aims/hypothesis. Patients with diabetes are characterised by endothelial dysfunction and cardiovascular mortality. In particular endothelium-derived nitric oxide has emerged as a first line mechanism against atherosclerosis. Hyperglycaemia causes oxygen radical stress but has also been associated with endothelial nitric oxide synthase uncoupling, both lead to decreased nitric oxide-availability. We recently showed that folate reverses eNOS uncoupling in vitro. Therefore we hypothesise that folate improves endothelial function in Type II (non-insulin-dependent) diabetes mellitus in vivo. Methods. Using forearm plethysmography, we evaluated the effect of local, intra-arterial administration of 5-methyltetrahydrofolate (5-MTHF, the active form of folic acid, 1 μg/100 ml FAV/min) on forearm blood flow in 23 patients with Type II diabetes and 21 control subjects, matched for age, sex, blood pressure, body mass index, weight and smoking habits. Serotonin as a stimulator of nitric oxide-dependent vasodilation and sodium nitroprusside as a stimulator of endothelium-independent vasodilation were infused. Results. Serotonin-induced vasodilation was blunted (53±30 vs 102±66 M/C%, p<0.005) and nitroprusside-induced vasodilation was mildly reduced (275±146 vs 391±203 M/C%, p<0.05) in patients with Type II diabetes compared to control subjects. 5-MTHF improved nitric oxide-mediated vasodilation (from 53±30 to 88±59 M/C%, p<0.05) in patients with Type II diabetes mellitus. As expected, 5-MTHF had no effect on forearm blood flow in control subjects. Conclusion/interpretation. These data imply that folate can be used to improve nitric oxide status and to restore endothelial dysfunction in patients with Type II diabetes. Our results provide a strong rationale for the initiation of studies that investigate whether supplementation with folic acid prevents future cardiovascular events in this patient group.",

keywords = "Blood Pressure Diabetes Mellitus, Type 2/blood/*physiopathology Endothelium, Vascular/*drug effects/physiology/physiopathology Female Folic Acid/*pharmacology Heart Rate Hematinics/*pharmacology Humans Male Middle Aged Nitric Oxide/*physiology Nitroprusside/pharmacology Reference Values Serotonin/pharmacology Vasodilation/*drug effects/physiology",

author = "{van Etten}, R.W. and {de Koning}, E. and M. Verhaar and C. Gaillard and T. Rabelink",

note = "M1 - 7 van Etten, R W de Koning, E J P Verhaar, M C Gaillard, C A J M Rabelink, T J eng Clinical Trial Comparative Study Controlled Clinical Trial Germany 2002/07/24 10:00 Diabetologia. 2002 Jul;45(7):1004-10. Epub 2002 Jun 6.",

year = "2002",

doi = "10.1007/s00125-002-0862-1",

language = "English",

volume = "45",

pages = "1004--1010",

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T1 - Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate

AU - van Etten, R.W.

AU - de Koning, E.

AU - Verhaar, M.

AU - Gaillard, C.

AU - Rabelink, T.

N1 - M1 - 7 van Etten, R W de Koning, E J P Verhaar, M C Gaillard, C A J M Rabelink, T J eng Clinical Trial Comparative Study Controlled Clinical Trial Germany 2002/07/24 10:00 Diabetologia. 2002 Jul;45(7):1004-10. Epub 2002 Jun 6.

PY - 2002

Y1 - 2002

N2 - Aims/hypothesis. Patients with diabetes are characterised by endothelial dysfunction and cardiovascular mortality. In particular endothelium-derived nitric oxide has emerged as a first line mechanism against atherosclerosis. Hyperglycaemia causes oxygen radical stress but has also been associated with endothelial nitric oxide synthase uncoupling, both lead to decreased nitric oxide-availability. We recently showed that folate reverses eNOS uncoupling in vitro. Therefore we hypothesise that folate improves endothelial function in Type II (non-insulin-dependent) diabetes mellitus in vivo. Methods. Using forearm plethysmography, we evaluated the effect of local, intra-arterial administration of 5-methyltetrahydrofolate (5-MTHF, the active form of folic acid, 1 μg/100 ml FAV/min) on forearm blood flow in 23 patients with Type II diabetes and 21 control subjects, matched for age, sex, blood pressure, body mass index, weight and smoking habits. Serotonin as a stimulator of nitric oxide-dependent vasodilation and sodium nitroprusside as a stimulator of endothelium-independent vasodilation were infused. Results. Serotonin-induced vasodilation was blunted (53±30 vs 102±66 M/C%, p<0.005) and nitroprusside-induced vasodilation was mildly reduced (275±146 vs 391±203 M/C%, p<0.05) in patients with Type II diabetes compared to control subjects. 5-MTHF improved nitric oxide-mediated vasodilation (from 53±30 to 88±59 M/C%, p<0.05) in patients with Type II diabetes mellitus. As expected, 5-MTHF had no effect on forearm blood flow in control subjects. Conclusion/interpretation. These data imply that folate can be used to improve nitric oxide status and to restore endothelial dysfunction in patients with Type II diabetes. Our results provide a strong rationale for the initiation of studies that investigate whether supplementation with folic acid prevents future cardiovascular events in this patient group.

AB - Aims/hypothesis. Patients with diabetes are characterised by endothelial dysfunction and cardiovascular mortality. In particular endothelium-derived nitric oxide has emerged as a first line mechanism against atherosclerosis. Hyperglycaemia causes oxygen radical stress but has also been associated with endothelial nitric oxide synthase uncoupling, both lead to decreased nitric oxide-availability. We recently showed that folate reverses eNOS uncoupling in vitro. Therefore we hypothesise that folate improves endothelial function in Type II (non-insulin-dependent) diabetes mellitus in vivo. Methods. Using forearm plethysmography, we evaluated the effect of local, intra-arterial administration of 5-methyltetrahydrofolate (5-MTHF, the active form of folic acid, 1 μg/100 ml FAV/min) on forearm blood flow in 23 patients with Type II diabetes and 21 control subjects, matched for age, sex, blood pressure, body mass index, weight and smoking habits. Serotonin as a stimulator of nitric oxide-dependent vasodilation and sodium nitroprusside as a stimulator of endothelium-independent vasodilation were infused. Results. Serotonin-induced vasodilation was blunted (53±30 vs 102±66 M/C%, p<0.005) and nitroprusside-induced vasodilation was mildly reduced (275±146 vs 391±203 M/C%, p<0.05) in patients with Type II diabetes compared to control subjects. 5-MTHF improved nitric oxide-mediated vasodilation (from 53±30 to 88±59 M/C%, p<0.05) in patients with Type II diabetes mellitus. As expected, 5-MTHF had no effect on forearm blood flow in control subjects. Conclusion/interpretation. These data imply that folate can be used to improve nitric oxide status and to restore endothelial dysfunction in patients with Type II diabetes. Our results provide a strong rationale for the initiation of studies that investigate whether supplementation with folic acid prevents future cardiovascular events in this patient group.

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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

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