Nitric oxide synthesis and isoprostane production in subjects with type 1 diabetes and normal urinary albumin excretion.
The role of nitric oxide (NO) and free radicals in the development of microvascular disease in type 1 diabetes remains unclear. We have measured NO and isoprostane (a stable marker of in vivo lipid peroxidation) production in 13 type 1 diabetic subjects with normal urinary albumin excretion and 13 healthy volunteers. Whole-body NO synthesis was quantified by measuring the urinary excretion of 15N-nitrate after the intravenous administration of L-[15N]2-arginine. The urinary excretion of the major urinary metabolite of 15-F2t-isoprostane (8-iso-prostaglandin-F2alpha), 2,3-dinor-5,6-dihydro-F2t-IsoP, was quantified as a marker of in vivo lipid peroxidation. Whole-body NO synthesis was significantly higher in diabetic subjects compared with control subjects (342 vs. 216 nmol 15N-nitrate/mmol creatinine [95% CI of the difference 45-207], P = 0.005). This increase was not explained by a difference in renal function between the 2 groups. There was no difference in 2,3-dinor-5,6-dihydro-F2t-IsoP excretion between diabetic subjects and control subjects (44.8+/-7.8 vs. 41.4+/-10.0 ng/mmol creatinine, mean +/- 95% CI). However, there was an inverse correlation between NO synthesis and free radical activity in subjects with diabetes (r = -0.62, P = 0.012) that was not observed in control subjects (r = 0.37, P = 0.107). We conclude that whole-body NO synthesis is higher in type 1 diabetic subjects with normal urinary albumin excretion than in control subjects. The inverse correlation between isoprostane production and NO synthesis in diabetic subjects is consistent with the hypothesis that NO is being inactivated by reactive oxygen species.
O'Byrne
S
S
Department of Clinical Pharmacology, St Bartholomew's and the Royal London School of Medicine and Dentistry, Charterhouse Square, UK. s.r.o'byrne@mds.qmw.ac.uk
Forte
P
P
Roberts
L J
LJ
Morrow
J D
JD
Johnston
A
A
Anggård
E
E
Leslie
R D
RD
Benjamin
N
N
D000328:Adult; D000419:Albuminuria; D003404:Creatinine / Q000652:urine; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000652:urine; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000652:urine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000096:biosynthesis*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012016:Reference Values; D012727:Sex Characteristics
C411579:2,3-dinor-5,6-dihydro-8-iso-prostaglandin F2(alpha); D009566:Nitrates; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D003404:Creatinine; D015237:Dinoprost