In vivo formation of 8-iso-prostaglandin F-2 alpha and platelet activationin diabetes mellitus - Effects of improved metabolic control and vitamin Esupplementation

Background-Diabetes mellitus (DM) is associated with enhanced lipid peroxid ation and persistent platelet activation. We tested the hypothesis that the in vivo formation of the F-2-isoprostane 8-iso-prostaglandin (PG)F-2 alpha , a bioactive product of arachidonic acid peroxidation, is enhanced in DM a nd contributes to platelet activation. Methods and Results-Urine samples were obtained from 85 diabetic patients a nd 85 age- and sex-matched healthy subjects for measurement of immunoreacti ve 8-iso-PGF(2 alpha) and 11-dehydro-thromboxane B-2 (TXM), an in vivo inde x of platelet activation. Sixty-two had non-insulin-dependent (NID)DM, and 23 had insulin-dependent (ID) DM, Vitamin E supplementation, metabolic cont rol, and cyclooxygenase inhibitors were used to investigate the mechanisms of formation of 8-iso-PGF(2 alpha) in this setting. Urinary 8-iso-PGF(2 alp ha) excretion was significantly higher (P=0.0001) in NIDDM patients (419 +/ - 208 pg/mg creatinine; range 160 to 1014) than in age-matched control subj ects (208 +/- 92; 41 to 433), Urinary 8-iso-PGF(2 alpha) was linearly corre lated with blood glucose and urinary TXM. 8-iso-PGF(2 alpha) 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 supplement ation (600 mg/d for 14 days) was associated with a statistically significan t reduction in both urinary 8-iso-PGF(2 alpha) (by 37%) and TXM (by 43%) in 10 NIDDM patients. Improved metabolic control was associated with a signif icant (P=0.0001) reduction in 8-iso-PGF(2 alpha) and TXM excretion by 32% a nd 41%, respectively, in 21 NIDDM patients. 8-iso-PGF(2 alpha) was unchange d after 2-week dosing with aspirin and indobufen despite profound suppressi on of TXM excretion. Conclusions-We conclude that DM is associated with increased formation of F -2-isoprostanes, as a correlate of impaired glycemic control and enhanced l ipid peroxidation. This may provide an important biochemical link between i mpaired glycemic control and persistent platelet activation. These results provide a rationale for dos-finding studies of antioxidant treatment in dia betes.