11-dehydro-thromboxane-b2 and Diabetes-Mellitus--Type-1

Topics: Adult; Arachidonate 5-Lipoxygenase; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Leukotriene E4; Male; Middle Aged; Oxidative Stress; Thromboxane B2

To investigate early events possibly related to the development of diabetic angiopathy, we examined whether 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) formation, a marker of in vivo oxidant stress, is altered in different stages of type 1 diabetes (T1DM) and whether it correlates with the rate of thromboxane (TX) A2 biosynthesis, a marker of in vivo platelet activation. We also investigated the relationship between inflammatory markers and F2-isoprostane formation in this setting.. A cross-sectional study was performed in 23 insulin-treated patients aged <18 years with new-onset T1DM (1 year, group B). Urinary 8-iso-PGF2alpha and 11-dehydro-TXB2 were measured in all patients and in age- and gender-matched controls. Circulating interleukin-6 (IL-6), tumor necrosis factor-alpha, and C-reactive protein were also determined as markers of the inflammatory response. Fifteen of the 23 children in group A were reexamined after 12 months. Compared with either controls or group B, diabetic children in group A showed significantly higher levels of 8-iso-PGF2alpha, 11-dehydro-TXB2, IL-6, tumor necrosis factor-alpha, and C-reactive protein. Statistically significant correlations between IL-6 and both 8-iso-PGF2alpha (r=0.63, P<0.001) and 11-dehydro-TXB2 (r=0.51, P<0.01) were observed. The 15 patients reexamined after 1 year showed a significant reduction in lipid peroxidation and platelet activation (P<0.02 and P<0.001, respectively), consistent with reduced levels of IL-6 and tumor necrosis factor-alpha.. These results demonstrate that enhanced lipid peroxidation and platelet activation represent early events in T1DM that are possibly related to an acute inflammatory response. These noninvasive indexes may help in further examining T1DM pathophysiology and monitoring pharmacological interventions to interfere with disease development and progression.

Topics: Adolescent; Biomarkers; C-Reactive Protein; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Dinoprost; Disease Progression; F2-Isoprostanes; Female; Follow-Up Studies; Humans; Inflammation; Insulin; Interleukin-6; Lipid Peroxidation; Male; Oxidative Stress; Platelet Activation; Reference Values; Thromboxane A2; Thromboxane B2; Time; Tumor Necrosis Factor-alpha

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.. 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.. 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.

Topics: Adult; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dinoprost; F2-Isoprostanes; Female; Humans; Lipid Peroxidation; Male; Middle Aged; Platelet Activation; Thromboxane B2; Vitamin E

Because pregnant women with diabetes have an increased risk of preeclampsia, we tested the hypothesis that urinary excretion of thromboxane metabolites is increased in diabetic pregnancies without evidence of preeclampsia at the time of testing.. Urinary excretion of thromboxane A2 metabolites (either 2,3-dinor-thromboxane B2 or 11-dehydro-thromboxane B2) was measured in 24 type I pregnant diabetic individuals and in 20 women with normal pregnancies between 28 and 32 weeks' gestation.. The amount of 2,3-dinor-thromboxane B2 and 11-dehydro-thromboxane B2 in the urine of pregnant women with diabetes (1727 +/- 415 and 827 +/- 276 pg/mg creatinine) was significantly higher than in women with normal pregnancies (638 +/- 218 and 178 +/- 145 pg/mg creatinine) (p < 0.002 and p < 0.001).. Our findings support a role for thromboxane in the pathogenesis of preeclampsia.

Topics: Diabetes Mellitus, Type 1; Female; Gestational Age; Humans; Pre-Eclampsia; Pregnancy; Pregnancy in Diabetics; Thromboxane B2

It has been speculated that platelet activation may contribute to the evolution of vascular complications in patients with Type I diabetes mellitus. To address this hypothesis, we measured the plasma and urinary metabolites of thromboxane, presumably of platelet origin, and of prostacyclin, derived from endothelial cells, in addition to more conventional indexes of platelet function. Urinary excretion of the metabolites 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha did not differ between diabetics with or without retinopathy and nondiabetic controls. Furthermore, measurement of platelet granule constituents, the aggregation responses to ADP or arachidonic acid, and levels of serum thromboxane B2 failed to discriminate between the groups. The institution of tight diabetic control with multiple daily injections of insulin failed to alter either urinary metabolite excretion or plasma levels of 11-dehydro-thromboxane B2. Conversely, insulin-induced hypoglycemia failed to alter the concentrations of plasma or urinary thromboxane metabolites in nondiabetic volunteers, despite a mean 60-fold increase in plasma epinephrine. These studies suggest that platelet activation does not precede the development of microvascular complications in patients with Type I diabetes who lack clinical evidence of macrovascular disease and have normal renal function. Furthermore, it is unlikely that platelet activation due to intermittent hypoglycemia contributes to the reportedly accelerated development of retinopathy in such patients, when they are subject to tight diabetic control.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Blood Platelets; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Epoprostenol; Humans; Insulin; Platelet Aggregation; Thromboxane B2; Thromboxanes