In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation.
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 F2-isoprostane 8-iso-prostaglandin (PG)F2alpha, a bioactive product of arachidonic acid peroxidation, is enhanced in DM and contributes to platelet activation.


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.
Davì
G
G
Departments of Medicine and Aging, University of Chieti "G. D'Annunzio" School of Medicine, Catholic University School of Medicine,Rome, Italy.
Ciabattoni
G
G
Consoli
A
A
Mezzetti
A
A
Falco
A
A
Santarone
S
S
Pennese
E
E
Vitacolonna
E
E
Bucciarelli
T
T
Costantini
F
F
Capani
F
F
Patrono
C
C
D000328:Adult; D003920:Diabetes Mellitus / Q000097:blood* / Q000378:metabolism* / Q000628:therapy; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000378:metabolism / Q000628:therapy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism / Q000628:therapy; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000652:urine; D028441:F2-Isoprostanes; D005260:Female; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000502:physiology*; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine; D014810:Vitamin E / Q000494:pharmacology*
D028441:F2-Isoprostanes; D014810:Vitamin E; C075750:8-epi-prostaglandin F2alpha; D013929:Thromboxane B2; C049235:11-dehydro-thromboxane B2; D015237:Dinoprost