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

Diabetologia. 2002 Jul;45(7):1004-10. doi: 10.1007/s00125-002-0862-1. Epub 2002 Jun 6.


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 microg/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.

Publication types

  • Clinical Trial
  • Comparative Study
  • Controlled Clinical Trial

MeSH terms

  • Blood Pressure
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / physiology
  • Endothelium, Vascular / 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*
  • Vasodilation / physiology


  • Hematinics
  • Nitroprusside
  • Nitric Oxide
  • Serotonin
  • Folic Acid