title: Abnormal metabolic fate of nitric oxide in Type I diabetes mellitus.
abstract: OBJECTIVE
  Reduced bioavailability of endothelium-derived nitric oxide is implicated in diabetic macrovascular and microvascular disease. In patients with diabetes, we hypothesised that protein glycosylation can alter nitric oxide binding affinity of haemoglobin and plasma proteins, hence reducing nitric oxide availability and causing an alteration in nitric oxide metabolism.
  
  
  METHODS
  Binding of nitric oxide to haemoglobin was studied across a range of glycosylation levels in vitro (HbA(1c) 5.9 to 9.8%). In clinical studies nitrate, nitrite, nitrosyl haemoglobin and plasma nitrosothiols were measured in venous blood from 23 patients with uncomplicated Type I (insulin-dependent) diabetes mellitus and 17 non-diabetic control subjects. Samples were analysed at baseline and after nitric oxide was added ex vivo.
  
  
  RESULTS
  Nitric oxide-haemoglobin binding was increased at a HbA(1c) greater than 8.5% compared with 5.9% (p<0.01). Basal nitrosyl haemoglobin was higher in diabetic patients compared with the control subjects (0.59+/-0.12 micro mol/l vs 0.24+/-0.12 micro mol/l, p<0.05). Plasma nitrosothiols, and nitrite and nitrate (NOx) concentrations were similar in diabetic patients compared with the control subjects (7.64+/-0.79 micro mol/l vs 5.93+/-0.75 micro mol/l, 13.98+/-2.44 micro mol/l vs 12.44+/-2.15 micro mol/l, respectively). In blood from diabetic patients, added nitric oxide was metabolised preferentially to nitrosyl haemoglobin and plasma nitrosothiols, with a twofold increase in nitrosyl haemoglobin observed across all concentrations of nitric oxide (p<0.05). These preferential increases correlated positively with HbA(1c).
  
  
  CONCLUSIONS
  Nitrosyl haemoglobin is increased in patients with Type I diabetes. Preferential metabolism to nitrosyl haemoglobin and nitrosothiols occurs after increases in nitric oxide. Our results show an accentuated association between nitric oxide and glycosylated proteins, especially deoxygenated haem. An altered metabolic fate of nitric oxide could influence microvascular regulation and tissue perfusion.
authors.affiliation: Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff, UK.
authors.forename: A B
authors.initials: AB
authors.lastname: Milsom
authors.forename: C J H
authors.initials: CJ
authors.lastname: Jones
authors.forename: J
authors.initials: J
authors.lastname: Goodfellow
authors.forename: M P
authors.initials: MP
authors.lastname: Frenneaux
authors.forename: J R
authors.initials: JR
authors.lastname: Peters
authors.forename: P E
authors.initials: PE
authors.lastname: James
mesh_terms: D000328:Adult; D017668:Age of Onset; D001682:Biological Availability; D001786:Blood Glucose / Q000378:metabolism; D001800:Blood Specimen Collection / Q000379:methods; D002784:Cholesterol / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D004578:Electron Spin Resonance Spectroscopy; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006031:Glycosylation; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D009573:Nitrites / Q000097:blood; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D002784:Cholesterol; D006442:Glycated Hemoglobin; D006454:Hemoglobins; D009566:Nitrates; D009569:Nitric Oxide; D009573:Nitrites; D014280:Triglycerides; C058377:hemoglobin A, glycosylated-nitric oxide complex