Diabetes mellitus (DM) is associated with enhanced lipid peroxidation and persistent platelet activation. We tested the hypothesis that the in vivo formation of the
F2-isoprostane 8-iso-prostaglandin (PG)F2alpha, a bioactive product of
arachidonic acid peroxidation, is enhanced in DM and contributes to platelet activation.
METHODS AND RESULTS: Urine samples were obtained from 85 diabetic patients and 85 age- and sex-matched healthy subjects for measurement of immunoreactive
8-iso-PGF2alpha and
11-dehydro-thromboxane B2 (TXM), an in vivo index of platelet activation. Sixty-two had non-
insulin-dependent (NID)DM, and 23 had
insulin-dependent (ID) DM.
Vitamin E supplementation, metabolic control, and
cyclooxygenase inhibitors were used to investigate the mechanisms of formation of
8-iso-PGF2alpha in this setting. Urinary
8-iso-PGF2alpha excretion was significantly higher (P=0.0001) in
NIDDM patients (419+/-208 pg/mg
creatinine; range 160 to 1014) than in age-matched control subjects (208+/-92; 41 to 433). Urinary
8-iso-PGF2alpha was linearly correlated with
blood glucose and urinary TXM.
8-iso-PGF2alpha excretion was also significantly (P=0. 0001) higher in
IDDM patients (400+/-146; 183 to 702) than in control subjects (197+/-69; 95 to 353).
Vitamin E supplementation (600 mg/d for 14 days) was associated with a statistically significant reduction in both urinary
8-iso-PGF2alpha (by 37%) and TXM (by 43%) in 10
NIDDM patients. Improved metabolic control was associated with a significant (P=0.0001) reduction in
8-iso-PGF2alpha and TXM excretion by 32% and 41%, respectively, in 21
NIDDM patients.
8-iso-PGF2alpha was unchanged after 2-week dosing with
aspirin and
indobufen despite profound suppression of TXM excretion.
CONCLUSIONS: We conclude that DM is associated with increased formation of
F2-isoprostanes, as a correlate of impaired
glycemic control and enhanced lipid peroxidation. This may provide an important biochemical link between impaired
glycemic control and persistent platelet activation. These results provide a rationale for dose-finding studies of
antioxidant treatment in diabetes.