In Vivo Formation of 8-Iso-Prostaglandin F 2α and Platelet Activation in Diabetes Mellitus

Abstract

Background —Diabetes mellitus (DM) is associated with enhanced lipid peroxidation and persistent platelet activation. We tested the hypothesis that the in vivo formation of the F 2 -isoprostane 8-iso-prostaglandin (PG)F 2α , 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-PGF 2α and 11-dehydro-thromboxane B 2 (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-PGF 2α in this setting. Urinary 8-iso-PGF 2α 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-PGF 2α was linearly correlated with blood glucose and urinary TXM. 8-iso-PGF 2α 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-PGF 2α (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-PGF 2α and TXM excretion by 32% and 41%, respectively, in 21 NIDDM patients. 8-iso-PGF 2α 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 F 2 -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.