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

Excessive oxidative stress due to hyperglycemia and glycoxidation leads to an increased production of F2-isoprostanes, one of which, 8-iso-PGF2 alpha, reaches high concentrations in plasma and urine in both insulin-dependent and non-insulin-dependent diabetics. This is associated with an increase in platelet activation, reflected by an increased urinary excretion of platelet-derived TxB2. Improved metabolic control or vitamin E supplementation reduces urinary 8-iso-PGF2 alpha and TxB2, whereas aspirin or indobufen reduces TxB2 but not 8-iso-PGF2 alpha. Since TxB2 in the urine seems to represent the common link between diabetes (as well as other risk factors) and the thrombotic complications of vascular disease, platelet activation due to lipid-glycoxidation is an important aspect in the pathogenesis of vascular complications of diabetes mellitus. Among the various plasma coagulation and fibrinolysis factors that are found to be altered in diabetes, the increased level of plasminogen activator inhibitor (PAI-1) in the plasma and in the vessel wall is of the utmost importance. Indeed, it is suspected that the atherosclerotic plaques formed in the presence of high concentrations of PAI-1 are more prone to rupture and ensuing thrombosis. The thrombosis-oriented modifications of blood platelets, coagulation and fibrinolysis are an important cause behind the high prevalence of vascular events in diabetes.

Topics: Blood Coagulation Factors; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Fibrinolysis; Glycosylation; Humans; Oxidative Stress; Plasminogen Activator Inhibitor 1; Platelet Activation; Risk Factors; Thrombosis; Thromboxane B2

Serum creatinine, immunoreactive serum and urine beta-2-microglobulin, plasma and urine thromboglobulin, plasma thromboxane-B2 levels and daily protein excretion were determinated in 61 insulin treated diabetic patients, comparing the different patient groups (complication free, nephropathy without azotaemia and nephropathy with azotaemia) with the control subjects. In the groups of all diabetic patients plasma and urine beta-thromboglobulin and plasma thromboxane-B2 levels were higher that in the controls. There was a positive significant correlation between urine beta-thromboglobulin and beta-2-microglobulin in the group without complication, and between the plasma beta thromboglobulin and beta-2-microglobulin, and plasma beta thromboglobulin and thromboxane levels in the diabetic group with azotaemia. In contradiction to some previous assumptions, the increased level of plasma beta-thromboglobulin reflects a real platelet hyperactivation also in patients with diabetic nephropathy. At the same time urine beta-thromboglobulin also increases. Determination of urine beta-thromboglobulin is more simple with less possibility of methodological error.

Topics: beta 2-Microglobulin; beta-Thromboglobulin; Blood Platelets; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Humans; Proteinuria; Thromboxane B2

Topics: Alprostadil; beta-Thromboglobulin; Blood Glucose; Blood Platelets; Cholesterol; Diabetes Mellitus, Type 1; Diet; Fatty Acids; gamma-Linolenic Acid; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin; Linolenic Acids; Lipids; Phospholipids; Platelet Aggregation; Prostaglandins E; Thromboxane B2; Triglycerides

HbA1c only partially predicts vascular risk in patients with type 1 diabetes (T1D), and a role for blood glucose variability (BGV) is a matter of debate. For this reason, this study investigated the impact of an educational programme of flexible insulin therapy (FIT) on BGV and oxidative stress.. Tests were conducted on 30 adult T1D patients in a prospective, single-centre trial at baseline (M0), and at 3 and 6 months (M3 and M6, respectively) of the FIT programme to determine BGV, as reflected by mean amplitude of glycaemic excursions (MAGE), low blood glucose index (LBGI), lability index (LI), average daily risk range (ADRR), glycaemic lability (scored by two diabetologists), urinary leukotriene E4 (LTE4), 11-dehydro-thromboxane B2 (TXB2) and 8-iso-prostaglandin F2α (PGF2).. HbA1c (7.7 ± 0.9%), ADRR, MAGE, LBGI and LI did not change from M0 to M3 and M6, although ADRR and LBGI significantly improved at M3 and M6 in patients with the highest baseline indices (≥ 40 and ≥ 5, respectively). TXB2 declined at M6 (832 ± 625 vs. 633 ± 972 pg/mg; P=0.048), whereas LTE4 and PGF2 remained stable. ADRR showed the strongest correlation with glycaemic lability scores at all visits (r≥0.84, P<0.0001).. A FIT educational programme improved BGV only in patients with the highest baseline variability, and led to no changes in HbA1c, while ADRR closely correlated with glycaemic lability score. Our data do not support a relationship between BGV and oxidative stress in T1D patients, although the impact of variability on TXB2 deserves further investigation (ClinicalTrials.gov NCT00973492).

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Health Education; Humans; Insulin; Leukotriene E4; Male; Middle Aged; Oxidative Stress; Prospective Studies; Thromboxane B2

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

To study the effect of vitamin E supplementation on platelet hyperaggregability in type 1 diabetic patients.. Written informed consent according to the Institutional Review Board on Human Experimentation guidelines was obtained from diabetic patients (n = 29) and their age-matched normal siblings (n = 21) to participate in this study. Diabetic patients were supplemented with DL-alpha-tocopherol (vitamin E) capsule (orally, 100 IU/day) or placebo for 3 months in a double-blind clinical trial. Alternate diabetic patients were assigned to vitamin E or placebo during regular visits to the clinic. Fasting blood was collected from each diabetic patient before the start and after the vitamin E or placebo supplementation. Platelet aggregability was assessed by competitive enzyme-linked immunosorbent assay of the blood TxB2 (a stable thromboxane metabolite). Plasma vitamin E and MDA (malondialdehyde, a product of lipid peroxidation) was assessed by high-performance liquid chromatography. Data were analyzed statistically on 12 diabetic patients on vitamin E and 12 on placebo supplementation.. Diabetic patients (n = 29) had 62% higher (P < 0.05) levels of TxB2 and 15% higher levels (P < 0.05) of MDA in comparison to normal subjects (n = 21). Plasma TxB2 levels had a significant correlation with MDA levels (r = 0.45, P < 0.02) but not with the HbA1 (r = -0.08), glucose (r = -0.13), duration of diabetes (r = -0.04), or age (r = 0.12) of diabetic patients. Vitamin E supplementation lowered MDA levels by 30% (P < 0.04), TxB2 levels by 51% (P < 0.03), and triglyceride levels by 22% (P < 0.04) in diabetic patients. There were no differences in these parameters before versus after placebo supplementation.. The elevated blood level of TxB2 (hyperaggregability of platelets) is significantly related to the level of lipid peroxidation products (oxidative stress) in type 1 diabetic patients. Supplementation of modest doses of vitamin E (100 IU/day) significantly lowers blood TxB2 and lipid peroxidation products levels in type 1 diabetic patients.

Topics: Child; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 1; Dietary Supplements; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lipid Peroxides; Male; Malondialdehyde; Oxidative Stress; Platelet Aggregation; Thromboxane B2; Vitamin E

In a prospective study with cross-over design 20 patients with insulin-dependent diabetes mellitus of more than 2 years duration were treated for 6 months with continuous subcutaneous insulin infusion (CSII) and multiple insulin injections (MII). Metabolic control, platelet aggregability, thromboxane B2 levels in serum and plasma as well as antithrombin III (ATIII) activity and von Willebrand factor antigen were evaluated. A good metabolic control was obtained by both intensified regimens. No difference could be demonstrated between either platelet function tests or serum level of von Willebrand factor antigen during treatment with CSII and MII. However, the plasma level of ATIII activity was significantly higher (P less than 0.01) during MII treatment as compared to CSII treatment. There was no correlation between ATIII activity and daily insulin requirement or serum fructosamine. In conclusion, long-term metabolic control with MII has a favourable effect on ATIII activity in plasma. This may be important for a delay in onset and progression of diabetic vascular complications.

Topics: Adult; Antithrombin III; Diabetes Mellitus, Type 1; Female; Humans; Injections; Insulin; Insulin Infusion Systems; Male; Platelet Aggregation; Prospective Studies; Random Allocation; Thromboxane B2; von Willebrand Factor

Eleven insulin-dependent diabetics exhibiting a fair but less than ideal diabetic control (HbA1 = 10.0 +/- 0.6%) were submitted in a random order to two 6 week-study periods of: continuous subcutaneous insulin infusion (CSII) and optimized conventional insulin therapy. Plasma lipids, fatty acids in plasma lipids and platelet function were estimated at baseline and at the end of each study period. Declines in HbA1 were observed at the end of either CSII or conventional period compared with baseline, but the differences were only significant under CSII (P less than 0.02). Plasma lipids and apoproteins remained unchanged at the end of the two study periods compared with baseline. Both CSII and optimized conventional treatment were followed by a significant increase of arachidonate in plasma lipids. A deterioration of the platelet function estimated from ADP or epinephrine-induced platelet aggregation and TxB2 generation by platelets was found under optimized conventional treatment while the platelet function appears to be normal at baseline and under CSII. These data indicate that slight but not sufficient improvements of diabetic control can result in deterioration of the platelet function. It seems that these deleterious effects are mediated through an increased production of arachidonate and in turn of TxB2.

Topics: Adult; Apoproteins; Blood Glucose; Diabetes Mellitus, Type 1; Fatty Acids; Female; Glycated Hemoglobin; Humans; Insulin; Insulin Infusion Systems; Lipids; Male; Middle Aged; Phospholipids; Platelet Aggregation; Random Allocation; Thromboxane B2

Albumin excretion rates (AER) were measured in 30 insulin-dependent diabetics during a 16-week double-blind, randomised, placebo-controlled study of the specific thromboxane synthetase inhibitor UK-38,485.6 of 15 subjects in the active group had microalbuminuria (defined as mean pretreatment AER 20-150 micrograms/min); in these patients AER fell from 32 +/- 3 micrograms/min to 11 +/- 1 micrograms/min at 8 weeks and 9 +/- 1 micrograms/min at 16 weeks. The AER rose again (to 29 +/- 8 micrograms/min) within 12 weeks of stopping the drug. There was no significant change in the 10 patients with microalbuminuria who received placebo. There was a strong correlation between change from baseline values and the baseline values themselves in the active, but not in the placebo group, and the change from baseline differed significantly between the two groups. There was no change in glycosylated haemoglobin or mean blood glucose levels during the study. In a separate study UK-38,485 caused significant suppression of thromboxane B2 synthesis in diabetic and non-diabetic subjects.

Topics: Adult; Albuminuria; Clinical Trials as Topic; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Female; Humans; Imidazoles; Male; Middle Aged; Oxidoreductases; Thromboxane B2; Thromboxane-A Synthase

The root of Rehmannia glutinosa (Gaertn.) DC. has been used in China for more than 2000 years to treat various diseases including diabetes mellitus (DM) and its complications. Steamed rehmannia root (SRR) is one of the mainly used forms. During its preparation, the material has the chance to be exposed to microorganisms, particularly yeast. The aim of this study is to verify the effect of SRR on diabetes complications and the necessity of yeast exposure.. Water extract of SRR was incubated with alcohol yeast to obtain fermented SRR (FSRR). Alloxan-induced diabetic rats were administrated with medicated animal chows for 8 weeks. Urine volume, fasted blood glucose and food intake were monitored, and open field test and tail immersion test were conducted in the last week, plasma and urine samples were subjected to biochemical examinations.. In DM rats, defecation in open field test was found reduced, and tail flick latency in tail immersion test increased. In the meantime, urinary excretions of Na(+), K(+), aldosterone, albumin and creatinine increased, and plasma concentrations of Na(+), K(+) and creatinine reduced and those of aldosterone, TXB₂/6-Keto-PGF(1α) and urea nitrogen elevated. Most of these indicators were significantly improved by FSRR administration, but the effects of SRR were relatively inferior in several aspects. However, SRR and FSRR could not improve the typical symptoms of DM.. Our data demonstrated that both SRR and FSRR have no obvious hypoglycemic effect, but have the potential to prevent the onset and development of diabetes complications, and this function can be improved by yeast exposure.

Topics: 6-Ketoprostaglandin F1 alpha; Aldosterone; Alloxan; Angiotensin II; Animals; Behavior, Animal; Blood Urea Nitrogen; Creatinine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Fermentation; Male; Plant Extracts; Plant Roots; Potassium; Rats; Rats, Wistar; Rehmannia; Sodium; Steam; Thromboxane B2; Yeast, Dried

Inflammation is implicated in diabetes and cyclooxygenase (COX) is involved in vascular inflammatory processes, participating in both atherosclerosis and thrombosis. The aims were to determine whether levels of monocyte COX and plasma COX metabolites are increased in Type 1 diabetic patients and to determine whether these could be linked to histone hyperacetylation.. Monocytes from 19 Type 1 diabetic and 39 non-diabetic control subjects were probed for COX and acetylated histone H4 proteins by immunoblotting. Plasma COX metabolite levels [thromboxane B(2) (TXB(2)) and prostaglandin E(2) (PGE(2))] were determined by enzyme immunoassay.. Monocyte COX-2 expression was significantly up-regulated (1.3-fold) in diabetic relative to the non-diabetic control subjects and plasma PGE(2) was markedly elevated (2.7-fold). In diabetic subjects, monocyte acetylated histone H4 levels were significantly elevated; sub-group analysis indicated that the increased histone acetylation was found only in the complication-free group.. Results support increased inflammatory activity in Type 1 diabetes that involves COX-2 and increased prostaglandin production, which may predispose patients to cardiovascular events. The observation of elevated histone acetylation only in complication-free diabetic subjects suggests that this may be a protective mechanism. This merits further investigation as histone hyperacetylation has been associated with reduced expression of factors involved in vascular injury and remodelling.

Topics: Acetylation; Adult; Australia; Cross-Sectional Studies; Cyclooxygenase 2; Diabetes Mellitus, Type 1; Female; Histones; Humans; Male; Monocytes; Plasma; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Thromboxane B2; Up-Regulation

Previously, we observed that alloxan-induced in vitro cytotoxicity and apoptosis in an insulin secreting rat insulinoma, RIN, cells was prevented by prior exposure to prostaglandin (PG) E(1), PGE(2), PGI(2), PGF(1)(alpha), and PGF(3)(alpha) (P<0.05 compared to alloxan), whereas thromboxane B(2) (TXB(2)) and 6-keto-PGF(1)(alpha) were ineffective. In an extension of these studies, we now report that prior intraperitoneal administration of PGE(1), PGE(2), PGF(1)(alpha), and PGF(3)(alpha) prevented alloxan-induced diabetes mellitus in male Wistar rats, whereas PGI(2), TXB(2), and 6-keto PGF(1)(alpha) were not that effective. PGE(1), PGE(2), PGF(1)(alpha), and PGF(3)(alpha) not only attenuated chemical-induced diabetes mellitus but also restored the antioxidant status to normal range in red blood cells and pancreas. These results suggest that PGE(1), PGE(2), PGF(1)(alpha), and PGF(3)(alpha) can abrogate chemically induced diabetes mellitus in experimental animals and attenuate the oxidant stress that occurs in diabetes mellitus.

Topics: Alloxan; Alprostadil; Animals; Antioxidants; Blood Glucose; Body Weight; Catalase; Ceruloplasmin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dinoprostone; Erythrocytes; Glutathione Peroxidase; Glutathione Transferase; Injections, Intraperitoneal; Insulin; Lactic Acid; Lipid Peroxides; Male; Malondialdehyde; Nitric Oxide; Pancreas; Prostaglandins; Prostaglandins F; Rats; Rats, Wistar; Superoxide Dismutase; Thromboxane B2

To assess the antioxidant/non-antioxidant effects of a hydroxytyrosol (HT)-rich phenolic extract from olive mill wastewaters administered with a breakfast.. Five type I diabetic patients received 25 mg of HT the first day and 12.5 mg/day the following 3 days. Blood sampling was carried out at T(0) (baseline) and T(4d) just before the breakfast + HT administration and at time points 1, 2, 3 and 4 h after T(0). Urines (24-h) were collected from T(0) to T(4d). Baseline HbA1c was generally inferior to 10%, glycemia was within the range 6-24 mmol/l, whereas total cholesterol, HDL-chol and triglycerides were normal.. The major finding was the 46% decrease in the serum TXB(2) production after blood clotting at T(4d). Plasma vitamin A, E, beta-carotene were not changed. Vitamin C tended to increase (P = 0.075). Plasma antioxidant capacity was enhanced at T(0)+1 h only, whereas its main determinants (albumin, bilirubin, uric acid) were not modified. Urinary 8-isoPGF(2alpha) levels were highly variable and were not affected significantly by HT administration.. The major effect of HT accounts for an antiaggregating platelet action, leading to a possible prevention of thrombotic and microthrombotic processes.

Topics: Adult; Aged; Antioxidants; Diabetes Mellitus, Type 1; Dinoprost; Dose-Response Relationship, Drug; Humans; Male; Middle Aged; Olive Oil; Phenylethyl Alcohol; Plant Oils; Platelet Aggregation; Thromboxane B2; Time Factors; Waste Disposal, Fluid; Waste Products

Vascular complications are the leading causes of morbidity and mortality in diabetic patients. The contribution of platelets to thromboembolic complications is well documented, but their involvement in the initiation of the atherosclerotic process is of rising interest. Thus, the aim of the present study was to evaluate basal arachidonic acid metabolism in relation to the redox status of platelets in both type 1 and type 2 diabetic patients, in the absence of vascular complications, as compared with respective control subjects. For the first time, we show that basal thromboxane B(2), the stable catabolite of thromboxane A(2), significantly increased in resting platelets from both type 1 and type 2 diabetic patients (58 and 88%, respectively), whereas platelet malondialdehyde level was only higher in platelets from type 2 diabetic subjects (67%). On the other hand, both vitamin E levels and cytosolic glutathione peroxidase activities were significantly lower in platelets from diabetic patients as compared with respective control subjects. We conclude that platelet hyperactivation was detectable in well-controlled diabetic patients without complications. This abnormality was associated with increased oxidative stress and impaired antioxidant defense in particular in type 2 diabetic patients. These alterations contribute to the increased risk for occurrence of vascular diseases in such patients.

Topics: alpha-Tocopherol; Antioxidants; Blood Glucose; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Glutathione Peroxidase; Glycated Hemoglobin; Humans; Lipid Peroxidation; Lipoxygenase; Middle Aged; Platelet Activation; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Reference Values; Thromboxane B2; Triglycerides

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

Serum creatinine, immunoreactive serum and urine beta 2-microglobulin, plasma and urine thromboglobulin, plasma thromboxane-B2 levels and daily protein excretion were determined in 61 insulin-treated diabetic patients, comparing the different patient groups (complication free, nephropathy without and with azotaemia) with control subjects. In the groups of diabetic patients, plasma and urine beta-thromboglobulin (BTG) and plasma thromboxane-B2 levels were higher than in the controls. There was a significant positive correlation between urine BTG and beta 2-microglobulin in the group without complication, and between the plasma BTG and beta 2-microglobulin, and plasma BTG and thromboxane levels in the diabetic group with azotaemia. In contrast to some previous assumptions, the increased level of plasma BTG reflects a real platelet hyperactivation in patients with diabetic nephropathy. At the same time, urine BTG also increases. Determination of urine BTG is more simple with less possibility of methodological error.

Topics: Adult; beta 2-Microglobulin; beta-Thromboglobulin; Biomarkers; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Humans; Middle Aged; Platelet Activation; Thromboxane B2

Diabetes mellitus is associated with a high incidence of cardiovascular diseases not directly attributable to hyperlipidemia, smoking, or hypertension, but which in part may be explained by an enhanced tendency to thrombosis due to increased platelet activity. The aim of this study was to evaluate platelet function and compare the effectiveness of the antiplatelet drug aspirin on platelet aggregation in diabetic and nondiabetic subjects. Platelet aggregation and composition were examined in 20 male insulin-dependent diabetes mellitus (IDDM) patients and 20 nondiabetic control subjects matched for age and body mass index. All were normotensive with serum total cholesterol less than 6.5 mM. Although within the clinically acceptable normal range, blood pressure was significantly higher in diabetic patients (130/75 mmHg) than in control subjects (123/70 mmHg) (P less than 0.05). Serum thromboxane B2 and ex vivo aggregation of platelets in response to two doses of the agonists collagen and platelet-activating factor (PAF) were similar to nondiabetic subjects. However, after taking 100 mg/day aspirin for 5 days, platelet aggregation to collagen was reduced by 76% in control subjects compared to 56% in IDDM patients (P less than 0.001). Aspirin treatment also reduced the slope of the aggregation curve and increased the lag time (the period between the addition of collagen and the start of irreversible aggregation) significantly more in control than in diabetic platelets. This difference in platelet aggregation could not be attributed to differences in platelet serotonin or thromboxane A2 secretion, the latter being almost completely suppressed by aspirin in each group. Platelet aggregation to PAF was similar in both groups and was not affected by aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aspirin; Blood Pressure; Cholesterol; Collagen; Diabetes Mellitus, Type 1; Fatty Acids, Omega-3; Humans; Linoleic Acid; Linoleic Acids; Male; Membrane Fluidity; Phospholipids; Platelet Activating Factor; Platelet Aggregation; Platelet Aggregation Inhibitors; Reference Values; Thromboxane B2

Increased free radical activity may contribute to thrombosis via effects on platelet aggregation and the prostanoid balance. To investigate this further we studied 15 Type 1 diabetic patients with retinopathy, matched with uncomplicated Type 1 patients for age, duration of diabetes and HbA1, together with matched healthy non-diabetic control subjects. The oxidative effects of free radicals as total diene conjugates and lipid peroxides were measured, together with redox status extracellularly as plasma albumin-thiols and intracellularly as erythrocyte superoxide dismutase activity. Platelet count, aggregation of platelets in whole blood to collagen, thromboxane B2, and prostacyclin stimulating factor (PGI2SF) were also assessed. Free radicals measured as lipid peroxides were significantly higher (9.6 (8.1-11.6) mumol l-1 (median and interquartile range) in diabetic patients with retinopathy than in control subjects (8.1 (7.4-9.2) mumol l-1; p less than 0.05). There were also significant reductions in redox status both extracellularly as plasma albumin thiols (408 (383-473) vs 490 (456-517) mumol l-1, p less than 0.001) and intracellularly as erythrocyte superoxide dismutase activity (34 (27-41) vs 44 (36-51) g l-1, p less than 0.05) between patients with retinopathy and control subjects. Platelet counts were increased in diabetic patients with retinopathy (p less than 0.05), as was collagen-induced platelet aggregation (p less than 0.01). Prostacyclin stimulating factor was reduced in patients with retinopathy (p less than 0.05) and correlated within the plasma with lipid peroxides (r = -0.53, p less than 0.04) and albumin thiols (r = 0.64, p less than 0.01). The results suggest that diabetic patients, particularly with retinopathy, are under oxidative stress and have an increased thrombotic tendency with increased platelet reactivity and a reduction in prostacyclin stimulating factor.

Topics: Adult; Biological Factors; Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Lipid Peroxides; Male; Malondialdehyde; Reference Values; Serum Albumin; Sulfhydryl Compounds; Superoxide Dismutase; Thromboxane B2

Topics: Amylases; Biomarkers; Diabetes Mellitus, Type 1; Graft Rejection; Humans; Pancreas Transplantation; Pancreatic Juice; Thromboxane B2; Transplantation, Homologous

Topics: Amylases; Animals; Biomarkers; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dogs; Graft Rejection; Insulin; Pancreas Transplantation; Thromboxane B2; Transplantation, Homologous

Platelet function (as production of thromboxane B2 by platelets stimulated with collagen, and plasma beta-thromboglobulin) and thrombin activity (as plasma fibrinopeptide A) were investigated in eight young (mean age 27 +/- 3 SE years) male patients in which type 1 diabetes mellitus had been diagnosed 2 to 6 months previously. They were all in excellent stable metabolic control (mean HbA1c 5.6 +/- 0.4 SE %) and free from any complications. The haemostatic variables were assessed at rest and after cycloergometric exercise to exhaustion. When compared to age- and sex-matched healthy controls, patients showed higher beta-thromboglobulin, fibrinopeptide A and thromboxane B2 at rest. After exercise, plasma beta-TG increased only in the controls. Platelet and thrombin activation are present in the very early stages of type 1 diabetes mellitus, in the absence of any complications.

Topics: Adult; beta-Thromboglobulin; Blood Platelets; Collagen; Diabetes Mellitus, Type 1; Exercise; Fibrinopeptide A; Humans; Male; Platelet Activation; Thromboxane B2

Platelet aggregation, platelet cAMP levels and thromboxane B2 (TXB2) synthesis had been investigated in 40 diabetics (20 with microangiopathy and 20 without) and 24 normal controls. The washed platelets, but not platelet rich plasma (PRP), from the diabetics show greater sensitivity to aggregation in response to thrombin, collagen and arachidonic acid than controls (P less than 0.05). Platelets from the diabetics contain the significantly decreased cAMP levels (P less than 0.01) and synthesize the significantly greater amount of TXB2 (P less than 0.01) when induced by thrombin or collagen. Conversion of exogenously added arachidonic acid to TXB2 remained unchanged (P greater than 0.05). cAMP levels in platelets from the diabetics exhibited a significant negative linear correlation with thrombin- and collagen-induced TXB2 synthesis. There was no significant difference in platelet aggregation, platelet cAMP levels and platelet TXB2 synthesis between the diabetics with and without microangiopathy. It was suggested that in the diabetic platelets: The observed increase in platelet thromboxane A2 (TXA2) synthesis should be due to the increased activity of arachidonic acid-metabolizing system, most likely at phospholipase site; the elevated platelet TXA2 levels should inhibit platelet membrane-associated adenylate cyclase which lowered the cAMP levels in platelets; and this alternation should be the mechanism of platelet hyperaggregability, which might contribute in some way to diabetic microangiopathy.

Topics: Adult; Blood Platelets; Cyclic AMP; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Male; Middle Aged; Platelet Aggregation; Thromboxane B2

Triflusal (2-acetoxy-4-trifluormethylbenzoic acid) is a platelet-antiaggregant drug that selectively inhibits thromboxane synthesis with little effect on prostacyclin production. In this study, we evaluated the effect of 5-day administration of 900 mg/day triflusal on glomerular filtration rate (GFR), renal plasma flow (RPF), urinary albumin excretion (UAE), thromboxane B2 (TXB2), 6-ketoprostaglandin F1 alpha (PGF1 alpha), and PGE2 in nine normotensive insulin-dependent diabetic patients with UAE between 30 and 103 micrograms/min. Plasma TXB2 and plasma renin activity (PRA) were also determined. After administration of triflusal, we observed a reduction in microalbuminuria (59 +/- 25 vs. 33 +/- 22 micrograms/min, P less than 0.01), an increase in RPF (648 +/- 119 vs. 722 +/- 134 ml.min-1 x 1.73 m-2, P less than 0.01), and a reduction in filtration fraction (0.24 +/- 0.04 vs. 0.20 +/- 0.03, P less than 0.01). Triflusal produced a significant reduction in both plasma TXB2 (130 +/- 39 vs. 52 +/- 32 pg/ml, P less than 0.02) and urine TXB2 (523 +/- 249 vs. 312 +/- 11 pg/min, P less than 0.02), without changes in PRA and UAE of 6-keto-PGF1 alpha and PGE2. Metabolic control and arterial blood pressure did not change during the study. These results suggest that platelet-antiaggregant therapy can reduce microalbuminuria in diabetic patients. This effect could be mediated by a reduction in the transglomerular hydraulic pressure through a vasodilation of efferent arterioles secondary to renal thromboxane synthesis inhibition.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Albuminuria; Blood Glucose; Diabetes Mellitus, Type 1; Dinoprostone; Female; Glomerular Filtration Rate; Humans; Male; Platelet Aggregation Inhibitors; Renal Circulation; Renin; Salicylates; Thromboxane B2

The relationship of insulin antibodies, platelet-fixing soluble immune complexes and platelet associated IgG to in vitro platelet aggregation and thromboxane B2 synthesis was studied in a group of children with type 1 (insulin-dependent) diabetes mellitus. Insulin antibodies, through the formation of insulin anti-insulin platelet-fixing immune complexes, seem to increase the levels of platelet associated IgG and both insulin immunity and increased platelet associated IgG are associated with the highest degree of platelet aggregation and thromboxane synthesis. These data suggest a possible role of immune factors in the platelet disfunction of diabetic subjects. Both platelet abnormalities and immune factors have been thought to play a role in the pathogenesis of the late diabetic complications. In this paper data concerning a possible interaction between these two factors are presented.

Topics: Adenosine Diphosphate; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Child; Collagen; Diabetes Mellitus, Type 1; Epinephrine; Female; Humans; Immunoglobulin G; Immunoglobulins; In Vitro Techniques; Insulin Antibodies; Male; Platelet Activating Factor; Platelet Aggregation; Reference Values; Thromboxane B2

In order to determine whether glomerular hyperfiltration in diabetes is related to renal prostaglandin production we have studied the urinary excretion of PGE2, 6-keto-PGF1 alpha, and TXB2 in two sex, age and duration of diabetes matched groups of 9 and 10 Type 1 diabetic patients with either normal (mean 121, range 105-129 ml min-1 1.73 m-2) or supranormal glomerular filtration rate (154, 135-206 ml min-1 1.73 m-2). A group of 15 matched healthy volunteers served as control subjects. Urine was collected overnight for an uninterrupted period of at least 6 h. All studies in the patients were performed during insulin-induced sustained euglycaemia to prevent the confounding effect of variable degrees of blood glucose control on urinary prostaglandin excretion. Blood pressure was normal in all subjects. Urinary excretion of 6-keto-PGF1 alpha was significantly higher in the patients with glomerular hyperfiltration (median 17.1, range 4.5-33.6 ng h-1) than in those without (8.8, 1.5-13.8 ng h-1; p less than 0.05) or in normal control subjects (9.6, 5.2-15.5 ng h-1; p less than 0.05). No significant differences were found in the excretion rates of PGE2 and TXB2 between the three groups. Under conditions of controlled plasma glucose and insulin concentrations the urinary excretion of 6-keto-PGF1 alpha, the stable breakdown product of PGI2, a compound of endothelial, possibly glomerular, origin was elevated only in the diabetic patients with glomerular hyperfiltration.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Glucose; Diabetes Mellitus, Type 1; Glomerular Filtration Rate; Humans; Male; Middle Aged; Prostaglandins; Prostaglandins E; Thromboxane B2

A study was made on the inhibitory effect of triflusal (600 mg/d X 15) and acetylsalicylic acid (ASA, 400 mg/d X 15) on platelet aggregation in whole blood (WB) and platelet-rich plasma (PRP) induced by ADP (2.5 mumol/l), adrenaline (50 mumol/l), collagen (1 microgram/ml) and arachidonic acid (0.8 mmol/l), in 30 insulin-dependent diabetic patients without vascular complications. Determination was also made of the serum levels of thromboxane B2 (TxB2) and of the plasma levels of 6-keto-PGF1-alpha and of beta-thromboglobulin (B-TG). Both drugs exhibited higher inhibitory effects in WB than in PRP. In WB, a significant difference between triflusal and ASA was observed against ADP-induced aggregation (67% and 46% inhibition respectively, p less than 0.01). Both drugs strongly inhibit the formation of TxB2 in serum (85% and 99%, respectively). Triflusal does not significantly change the plasma levels of 6-keto-PGF1-alpha; ASA, by contrast, causes reduction of over 95% in those plasma levels. The plasma levels of B-TG were not modified by either of the drugs.

Topics: Adult; Aspirin; beta-Thromboglobulin; Diabetes Mellitus, Type 1; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandins F; Salicylates; Thromboxane B2

In 24 type I and 22 type II diabetic patients without vascular complications and in 25 controls platelet thromboxane A2 (TxA2) and prostaglandin E2 (PGE2) production (by radioimmunoassay-RIA) and 1-14C arachidonic acid (AA) metabolism (by high pressure liquid chromatography-HPLC) after thrombin stimulation were studied. Platelets both from type I and type II diabetics generated larger amounts of TxB2 (p less than 0.001) and PGE2 (p less than 0.005) than controls, independently of the presence of retinopathy. No significant differences in platelet AA uptake or metabolism via the cyclooxygenase (CO) route, after thrombin stimulation (5 NIH U/ml), were observed in diabetic patients: lipoxygenase metabolites were found to be slightly, but significantly decreased. A positive linear relationship (r = 0.64, p less than 0.001) was found between HbA-1c and TxB2 production, but not with fasting plasma glucose. These results indicate that metabolic alterations can affect platelet function independently of vascular complications. The absence of alterations in intraplatelet 1-14C AA metabolism via CO, in the presence of increased TxB2 and PGE2 production from endogenous AA, suggests that the activation of CO is not the only possible mechanism of platelet activation and that probably an increased availability of platelet AA plays an important role in the enhanced platelet aggregation commonly found in diabetics.

Topics: Adult; Blood Platelets; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dinoprostone; Female; Humans; Lipoxygenase; Male; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Radioimmunoassay; Thrombin; Thromboxane B2

To elucidate the bleeding tendency that follows the administration of ticlopidine, we investigated the skin bleeding time and some ex vivo functions of platelets from nine patients with insulin-dependent diabetes before and 2 weeks after daily doses of 500 mg ticlopidine. Ticlopidine significantly prolonged bleeding time and reduced platelet reactivity to fixed, relatively high concentrations of aggregating agents, without interfering with thromboxane B2 formation. We used a rotating probe device at a relatively low shear rate (570 sec-1) to measure platelet adhesion to human subendothelium. This system was able to detect an impairment of platelet adhesion dependent on glycoprotein (GP) Ib defect (Bernard Soulier syndrome) or on low platelet von Willebrand factor content, but was insensitive to platelet GPIIb-IIIa defect (Glanzmann's thrombasthenia). In our patients, platelet adhesion was consistently reduced after the administration of ticlopidine. We conclude that ticlopidine is an inhibitor of platelet function that modulates the interaction between platelets. The drug also appears to interfere with mechanisms that modulate platelet-subendothelium interaction at relatively low shear rates. This double action could be relevant in the prevention of vasculopathy in patients with diabetes.

Topics: Adult; Bleeding Time; Diabetes Mellitus; Diabetes Mellitus, Type 1; Endothelium, Vascular; Female; Fibronectins; Humans; Male; Middle Aged; Platelet Adhesiveness; Platelet Aggregation; Thromboxane B2; Ticlopidine

Low-density lipoprotein (LDL) is known to enhance platelet sensitivity to some aggregating agents. In this study, we observed that LDL isolated from patients with insulin-dependent diabetes mellitus (IDDM) enhanced thrombin-induced platelet aggregation to a greater extent than LDL isolated from matched controls (P less than .01). Thromboxane B2 production during aggregation was also significantly more enhanced by LDL isolated from IDDM than by control LDL (P less than .01). There was no difference in the lipid composition (free and esterified cholesterol, total phospholipids, and triglycerides) of LDL isolated from diabetic and control subjects. In contrast, the extent of glycosylation of LDL isolated from diabetic patients was significantly greater than that observed in LDL from normal subjects (P less than .01), and a positive correlation (r = .605, P less than .01) between the degree of LDL glycosylation and the rate of platelet aggregation was observed. LDL glycosylated in vitro enhanced thrombin-, collagen-, and adenosine 5'-diphosphate-induced platelet aggregation to a greater extent than control LDL (P less than .01). Although LDL glycosylated in vitro was taken up by platelets to a greater extent than control LDL (P less than .05), the lipid composition (free cholesterol and phospholipid) of platelets was not significantly changed. We postulate that an increased degree of glycosylation of LDL may enhance its uptake by platelets and lead to increased platelet reactivity to aggregating agents, probably by altering the structure of the platelet membrane. The enhancement of platelet aggregation by LDL may contribute to the accelerated development of atherosclerosis in diabetes mellitus.

Topics: Adolescent; Adult; Diabetes Mellitus, Type 1; Female; Glycosylation; Humans; Lipoproteins, LDL; Male; Phospholipids; Platelet Aggregation; 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

Numerous platelet abnormalities, particularly hyperaggregation, have been described in diabetic patients, and it has been suggested that these may contribute towards the pathogenesis of microvascular complications. In the present study, the changes that occur in ADP-induced aggregation, sensitivity to a stable prostacyclin analogue (Iloprost), aggregation-induced thromboxane B2 production and platelet cyclic AMP levels were investigated in 9 young insulin-dependent diabetics, in which the glycaemic control significantly improved in one group (n = 5; HbA1 from 11.9-9.0%) over a 6 month period. With improvement of glycaemic control there was no significant change in the concentration of ADP required to produce 50 percent of the maximum aggregation wave response. However, there was a significant increase in the responsiveness of platelets to Iloprost and increased platelet thromboxane B2 production. There was no significant difference between the basal platelet cAMP levels before or after exposure to Iloprost. This study suggests that with improved short-term glycaemic control, although there are changes in platelet function, there may be no alteration in the homeostatic balance.

Topics: Adenosine Diphosphate; Adult; Blood Glucose; Blood Platelets; Cyclic AMP; Diabetes Mellitus, Type 1; Epoprostenol; Humans; Iloprost; Male; Platelet Aggregation; Thromboxane B2; Time Factors

Topics: Adolescent; Adult; Blood Glucose; Blood Platelets; Diabetes Mellitus, Type 1; Epoprostenol; Fatty Acids, Unsaturated; Humans; Hypoglycemia; Insulin; Thromboxane B2

The capacity of prostacyclin production determined as plasma 6-keto-PGF1 alpha was investigated in 12 type 1 (insulin-dependent) diabetic patients with a median duration of diabetes of 14 years during ordinary metabolic control. Using high pressure liquid chromatography preceding radioimmunoassay, the plasma concentration of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin, was determined at rest and after a standardised bicycle exercise test. The plasma 6-keto-PGF1 alpha in diabetic patients at rest did not differ from that of 25 healthy volunteers; 2.9 pg/ml (range less than 0.2-15.3) versus 1.7 pg/ml (range less than 0.2-16.6). During the exercise test plasma 6-keto-PGF1 alpha increased significantly in the diabetic patients as well as in the control group (p less than 0.05). The increment of 6-keto-PGF1 alpha in the diabetic patients was neither related to the metabolic regulation, duration of diabetes nor to changes in platelet volume, platelet number or the production of thromboxane B2 and prostaglandin E2. Our results do not support the hypothesis that Type 1 diabetic patients have a decreased capacity of prostanoid production, as suggested from in vitro studies.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Diabetes Mellitus, Type 1; Dinoprostone; Female; Humans; Male; Middle Aged; Physical Exertion; Platelet Count; Prostaglandins E; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Platelets; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Reference Values; Thromboxane A2; Thromboxane B2

The effect of dihomogammalinolenic acid (DHLA) administration on platelet aggregation and prostaglandin production, erythrocyte fatty acid composition and serum lipids was compared in healthy subjects and insulin-dependent diabetics (IDDs). In healthy subjects, DHLA caused a significant inhibition of ADP-induced platelet aggregation and an increase in platelet PGE1 release; IDDs did not show these changes. There were no differences, however, in platelet thromboxane A2 (TXA2) or PGE2 release between healthy subjects and IDDs before and after DHLA. Following DHLA, the arachidonic acid content of erythrocytes increased in healthy subjects; this increase was not observed in IDDs. DHLA induced a significant fall in serum non-esterified fatty acid concentrations in both groups without altering either cholesterol or triglyceride concentrations. These data show for the first time that IDD platelets may have a specific defect of PGE1 synthesis quite distinct from the delta 5- and delta 6-desaturase defects known to be associated with experimental diabetes; this defect may contribute to platelet hyper-aggregability in diabetes; and DHLA has a potent antilipolytic effect in vivo; and erythrocytes from IDDs may have a delta 6-desaturase defect.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Alprostadil; beta-Thromboglobulin; Blood Glucose; Cholesterol; Delta-5 Fatty Acid Desaturase; Diabetes Mellitus, Type 1; Dinoprostone; Erythrocyte Membrane; Erythrocytes; Fatty Acid Desaturases; Fatty Acids; Fatty Acids, Nonesterified; Fatty Acids, Unsaturated; Female; Glycated Hemoglobin; Humans; Lipid Metabolism; Lipids; Male; Middle Aged; Platelet Aggregation; Platelet Factor 4; Prostaglandins; Prostaglandins E; Thromboxane B2; Triglycerides

Seventeen patients with insulin-dependent diabetes mellitus, all below the age of 45 years, were studied. Five of them had retinopathy but no other micro- or macrovascular diabetic complications. None of them had any other concurrent disorder or were on any medication but insulin. The results were compared to those of 17 healthy volunteers of comparable age. There was no difference between the two groups in venous platelet counts, serum production of thromboxane B2 (TXB2), ADP-induced platelet aggregation or bleeding times. As compared to the controls, the diabetics had significantly elevated blood glucose and glycosylated hemoglobin values. The mean plasma values of beta-thromboglobulin, platelet factor 4 and TXB2 were significantly lower in the patients than in the controls. Thus, our results do not lend support to the current concept that platelet reactivity is enhanced in diabetes mellitus.

Topics: Adenosine Diphosphate; Adolescent; Adult; beta-Thromboglobulin; Blood Platelets; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Male; Platelet Aggregation; Platelet Factor 4; Thromboxane B2

Platelets from diabetics are known to be more sensitive in vitro to a variety of aggregating agents, to produce more prostaglandin endoperoxides and thromboxane and to bind more 125I-fibrinogen than platelets from normal controls Fibrinogen binding to platelets is a pre-requisite for platelet aggregation. Previous studies suggested a role for prostaglandins and/or thromboxane A2 in the exposure of fibrinogen receptors on platelets. The present study compares fibrinogen receptors on platelets. The present study compares fibrinogen binding to hyperaggregable platelets from diabetic patients and to normal platelets when prostaglandin/thromboxane formation is suppressed by aspirin. It was found that pre-treatment with aspirin reduced collagen or thrombin-induced binding to platelets from non-retinopathic diabetics to the values seen in controls. By contrast, aspirin did not normalize binding to platelets obtained from retinopathic diabetics. The combination of aspirin with apyrase (an ADP scavenger) almost completely inhibited binding and aggregation of platelets from normal controls or non-retinopathic diabetics exposed to collagen or thrombin, whereas it only partially affected binding and aggregation of platelets from retinopathics. By using a monoclonal antibody (B59.2) to the platelet receptor for fibrinogen, we determined that this receptor was quantitatively and qualitatively the same on platelets from normal controls and diabetics. We conclude that increased fibrinogen binding and hyperaggregability of platelets from non-retinopathic diabetics is related to their capacity to form more prostaglandin endoperoxides/thromboxane than normal platelets. In contrast, hyperaggregability and increased binding of platelets from retinopathics appear at least partly related to a mechanism independent of ADP release and thromboxane synthesis.

Topics: Blood Platelets; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Fibrinogen; Humans; Platelet Aggregation; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Thromboxane B2

Platelet thromboxane B2 (TxB2) production, plasma concentrations of C-peptide and pancreatic glucagon as well as blood glucose levels were measured in 12 infants of insulin-dependent diabetic mothers and eight healthy controls at the age of two hours. Platelet TxB2 production (p less than 0.05) and plasma C-peptide levels (p less than 0.02) were significantly higher and blood glucose concentrations lower (p less than 0.002) in the infants of the diabetic mothers than in the controls. The data suggest that platelets of infants of diabetic mothers produce increased amounts of proaggregatory thromboxane A2, which may contribute to the hyperaggregation in these infants.

Topics: Blood Glucose; Blood Platelets; C-Peptide; Diabetes Mellitus, Type 1; Female; Fetal Blood; Glucagon; Humans; Infant, Newborn; Pancreas; Thromboxane B2

Some studies have recently reported increased production of platelet thromboxane and decreased vascular prostacyclin in patients with diabetes mellitus. The impact of these changes on platelet and vascular functions in vivo is still speculative. Using radio-immunoassay and high pressure liquid chromatography we have studied the plasma levels of 6-keto-PGF1 alpha, TXB2 and PGE2 in 23 juvenile-onset diabetics. There was no significant difference in these plasma prostaglandins between the diabetics and a control group. The prostaglandins were neither correlated to blood-glucose nor the degree of glycosylation (HbA1c). Our results can not support the hypothesis that decreased vascular prostacyclin and increased platelet production of TXB2 are important factors in diabetic patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 1; Dinoprostone; Female; Humans; Male; Middle Aged; Prostaglandins; Prostaglandins E; Radioimmunoassay; Thromboxane B2

Ten healthy and twenty diabetic volunteers (type 1) received 15 capsules (à 450 mg) cod liver oil for 2 weeks daily in addition to a "normal" diet. The levels of eicosapentaenoic acid in the plasma phospholipids of both groups were increased after the treatment. The inhibition of the prostacyclin formation by LDL was diminished when the LDL was isolated after the treatment in comparison to LDL taken in the same concentration and from the same donors before it. The thromboxane B2 (TXB2) synthesis capacity of clotting whole blood, thrombin-induced TXB2 formation by platelets as well as the 15(S)-hydroxy-11 alpha,9 alpha-epoxymethano-5Z, 13E-prostadienoic acid-induced platelet aggregation were not altered by the treatment in healthy volunteers, whereas in diabetics the TXB2 formation capacity of clotting whole blood was decreased after the treatment in comparison with before it.

Topics: Adult; Bleeding Time; Blood Platelets; Cod Liver Oil; Diabetes Mellitus, Type 1; Epoprostenol; Fatty Acids; Female; Fish Oils; Humans; Lipoproteins, LDL; Male; Malondialdehyde; Phospholipids; Platelet Aggregation; Thromboxane B2; Whole Blood Coagulation Time

Pharmacological studies have shown that the addition of somatostatin to insulin promotes a more rapid recovery from diabetic ketoacidosis. However, contradictory results have been reported concerning the action of somatostatin on platelet function, frequently deranged in diabetes. Therefore the plasma levels of thromboxane B2, a stable metabolite of proaggregatory thromboxane A2 and of beta-thromboglobulin, a marker of platelet activation, were studied in 9 control subjects and in 13 insulin-dependent diabetic patients before and during somatostatin injection, administered as an initial 250 micrograms iv bolus followed by infusion of 300 micrograms over 3 h. In both groups, after somatostatin infusion thromboxane B2 and beta-thromboglobulin levels showed, respectively, a progressive fall and an increase up to the second hour. Over the next hour thromboxane B2 increased and beta-thromboglobulin decreased but their levels did not return to basal values. During this experiment beta-thromboglobulin plasma values in diabetic patients did not differ from those of control subjects. In contrast, thromboxane B2, decreased in relation to pharmacological treatment, maintained elevated levels. Our data, however, demonstrate that the dose of somatostatin used, produced in the diabetic patients a normal fall of thromboxane B2 in terms of percentage of base-line values, but increases of beta-thromboglobulin lower than in control subjects. It is suggested that platelet function should be evaluated when somatostatin is used in the treatment of poorly controlled type I diabetes.

Topics: Adult; Beta-Globulins; beta-Thromboglobulin; Blood Glucose; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Female; Humans; Infusions, Parenteral; Male; Middle Aged; Somatostatin; Thromboxane B2; Thromboxanes

The purpose of our study was to investigate the connection between platelets and the contact phase of coagulation. In 17 patients affected by diabetes mellitus we studied the behaviour of prekallikrein, factor XII and factor XI before and after aspirin administration. To evaluate the activity of aspirin we measured platelet production of thromboxane B2 using a radioimmunoassay. In our diabetic patients a hypercoagulable state was confirmed: PK, factor XII and XI levels were significantly higher as compared with normal controls. After aspirin administration a significant decrease of PK levels was found. After 7 days of aspirin administration and 7 days after stopping aspirin a modest but not significant improvement of factor XII and factor XI was observed. In conclusion, we believe that the contact phase of coagulation is another index of the hypercoagulable state in diabetes mellitus. In addition, the decrease of PK obtained by aspirin administration could support the possible connection between the contact phase of coagulation and platelets.

Topics: Aspirin; Blood Coagulation; Blood Platelets; Diabetes Mellitus, Type 1; Factor XI; Factor XII; Female; Humans; Male; Middle Aged; Prekallikrein; Thromboxane B2

Previous studies suggested a role for prostaglandins or thromboxane A2, or both in the exposure of fibrinogen receptors on normal platelets in response to several aggregating agents. Platelets from diabetics are known to be more sensitive to aggregating agents and to produce more prostaglandins and thromboxane than platelets from normal subjects. We compared fibrinogen binding to platelets from diabetic subjects with binding to platelets from normal subjects and determined whether aspirin (which inhibits the formation of prostaglandins and thromboxane) would inhibit the binding of fibrinogen to platelets from diabetic subjects and whether this correlated with its effects on platelet aggregation. We found the following: Aspirin suppressed thromboxane formation and rendered the platelets less sensitive to the induction of aggregation by adenosine diphosphate (ADP) or collagen. The amount of U-46619 [( 15s]-hydroxy-11-alpha, 9-alpha [epoxy-methano]-prosta[5Z,13E]-dienoic acid, a stable analog of prostaglandin endoperoxide/thromboxane A2) necessary to induce aggregation, was similar in normal and diabetic subjects and was unchanged after ingestion of aspirin. Binding of 125I-fibrinogen following stimulation of platelets by ADP or collagen was greater in diabetic (because more binding sites were exposed) than in normal subjects. However, following stimulation by U-46619, binding was similar in diabetic and normal subjects. Aspirin caused a reduction in the exposure of binding sites on both platelets from diabetic and normal subjects, so that (in this respect) platelets from diabetic subjects became more like those from normal subjects. Effects of the monoclonal antibody B59.2, which is specific for the platelet glycoprotein IIb-IIIa complex (the presumed receptor for fibrinogen on the platelet surface) were also studied. The amount of this antibody that bound to platelets was the same for normal and diabetic subjects both before and after aspirin and with or without stimulation by ADP or collagen. In addition, B59.2 inhibited aggregation and fibrinogen binding in both platelets from diabetic and normal subjects. The combined data suggest that the glycoprotein IIb-IIIa complex of platelets from diabetic subjects is similar to that of platelets from normal subjects and that the increased fibrinogen binding and aggregation of platelets from diabetic subjects in response to ADP or collagen is mediated by increased formation of prostaglandin endoperoxide or thrombo

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Adenosine Triphosphate; Adolescent; Adult; Antibodies, Monoclonal; Binding Sites, Antibody; Binding, Competitive; Blood Platelets; Collagen; Diabetes Mellitus, Type 1; Female; Fibrinogen; Humans; In Vitro Techniques; Male; Platelet Aggregation; Platelet Membrane Glycoproteins; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Receptors, Cell Surface; Thromboxane B2

Patients with diabetes mellitus manifest increased in vitro platelet aggregation and increased synthesis of the proaggregant and vasoconstrictor, thromboxane A2 (TXA2). We studied the effects of continuous insulin infusion treatment on platelet aggregation and arachidonic acid (AA)-stimulated platelet TXA2 synthesis (15 and 30 s post-AA, 1 mM) in 16 type I diabetic patients. Strict glycemic control was induced with the Biostator for 2 days and maintained for 12-14 days with continuous subcutaneous insulin infusion (CSII). The average premeal plasma glucose level (4/day) fell from 184 +/- 15, before treatment, to 107 +/- 6 mg/dl on the final day (P less than 0.001). After control, platelet synthesis of TXA2, measured by radioimmunoassay of its stable metabolite, immunoreactive TXB2 (iTXB2), decreased in all patients (30 s: 276 +/- 31 versus 199 +/- 28 ng iTXB2/ml/5 X 10(5) platelets; P less than 0.05). The reduction in platelet iTXB2 synthesis (15 and 30 s) was greater in poorly controlled patients (HbA1c greater than 12%; N = 8), and for all patients the decrease in iTXB2 (15 and 30 s) was correlated with the prestudy HbA1c level (15 s: r = 0.6; P less than 0.01). In contrast, platelet aggregation responses did not improve during intensive insulin treatment. The ED50 for AA (dose producing 50% maximum aggregation at 1 min) was unchanged after 2 wk of treatment and the ED50 for aggregation induced by ADP fell significantly in patients with HbA1c greater than 12% (2.8 +/- 1.3 versus 1.2 +/- 0.6 microM; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Diphosphate; Adolescent; Adult; Arachidonic Acid; Arachidonic Acids; Blood Glucose; Blood Platelets; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Female; Humans; Insulin; Insulin Infusion Systems; Lipoproteins; Male; Middle Aged; Platelet Aggregation; Thromboxane A2; Thromboxane B2

Platelets from patients with type 1 diabetes have exhibited more sensitivity to aggregation when compared with platelets from controls without diabetes after challenge with platelet-activating factor (PAF). The production of thromboxane B2 (TxB2) and 12-hydroxyeicosatetraenoic acid (12-HETE) and the release of 5-hydroxytryptamine (5HT) were increased when the platelets were challenged by PAF (5.0 X 10(-6) mol/L and 1.0 X 10(-6) mol/L). The production of TxB2 and 12-HETE and the release of 5HT were related to the irreversible biphasic aggregation profiles observed in the patients with diabetes. Inhibition of thromboxane A2 (TxA2) production by acetylsalicylic acid abolished the secondary wave of aggregation of platelets from patients with diabetes, changing an irreversible aggregation to a reversible one. Inhibition of both TxA2 and 12-HETE production by eicosatetraynoic acid did not contribute further to the inhibition caused by acetylsalicylic acid alone, indicating that 12-HETE was not involved in the secondary wave of aggregation. These data show that the increased aggregation observed in the platelets from the group with diabetes in response to PAF results in part from their higher production of TxA2 and release of 5HT.

Topics: Adult; Blood Glucose; Carbon Radioisotopes; Cholesterol; Diabetes Mellitus, Type 1; Epinephrine; Female; Humans; Hydroxyeicosatetraenoic Acids; Male; Middle Aged; Platelet Activating Factor; Platelet Aggregation; Radioimmunoassay; Serotonin; Thromboxane B2; Triglycerides

Basal and two hours after 600 mg acetylsalicylic acid (ASA) bleeding times were measured in 21 type I diabetic patients with retinopathy, 24 type I diabetic patients without retinopathy and 21 normal healthy volunteers. There were no significant differences either in basal or in after ASA bleeding times between these groups, but the percentage increase in bleeding time after ASA was significantly higher than normal in both diabetic groups. No correlation was found between basal--bleeding time and glucose, Hb A1 or lipid profile. TXB2 production by spontaneous blood clotting was drastically reduced by ASA in both diabetic and normal groups. Platelet hyperactivity in diabetes mellitus may be due, at least in part, to a predominance of the proaggregatory effects of TXA2 over the antiaggregatory effects of PGI2.

Topics: Adolescent; Adult; Aspirin; Bleeding Time; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Lipids; Male; Thromboxane B2

Somatostatin, as an adjunct to insulin in the treatment of poorly controlled type 1 diabetes, has been recently suggested. However, some authors, after injection of the polypeptide, detected a reduction in number and aggregation of platelets, others instead, reported a proaggregatory effect of the drug. To answer these questions, the plasma levels of proaggregatory thromboxane A2 and of B-thromboglobulin, marker of the platelet activation, were studied in nine control subjects and in thirteen insulin dependent diabetic patients before and during the endovenous injection, for three hours, of somatostatin (250 micrograms in bolus followed by infusion of 100 micrograms/h). In both groups, 30 min after the infusion of somatostatin, a fall of thromboxane B2, stable metabolite of thromboxane A2 and an increase of B-thromboglobulin were respectively observed. Their greatest figure was reached after 120 min and their levels did not return to basal values within the end of the observation. In diabetics, during the infusion of somatostatin, thromboxane B2 presented normal percentual falls while B-thromboglobulin showed increases which were lower than controls. In conclusion, the effect of somatostatin implied in the relative lower increase of B-thromboglobulin, seems connected to the precedent continuous activation of circulating platelets, the one, responsible for the decrease of thromboxane B2, instead, seems linked to a direct action of somatostatin, independently on the deranged metabolic conditions found in diabetic patients.

Topics: Adult; Beta-Globulins; beta-Thromboglobulin; Blood Platelets; Diabetes Mellitus, Type 1; Female; Humans; Male; Middle Aged; Somatostatin; Thromboxane B2; Thromboxanes

11 insulin-dependent and 19 non insulin-dependent diabetics with varying degrees of metabolic compensation and with high plasma levels of beta-thromboglobulin and thromboxane B2 were selected. Depending on the type of diabetes and the degree of glycaemia, control plasma levels of beta-thromboglobulin and thromboxane B2 were progressively lower after 14, 28 and 42 days of treatment with ticlopidine (500 mg/per day orally), than those encountered at the start of the study. It is concluded that ticlopidine influences plasma levels of beta-thromboglobulin and thromboxane B2 independently of the type and degree of metabolic compensation in diabetes mellitus.

Topics: Beta-Globulins; beta-Thromboglobulin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Thiophenes; Thromboxane B2; Thromboxanes; Ticlopidine

The effect of improved glycaemic control, effected by 16 weeks continuous subcutaneous insulin infusion (CSII), on platelet aggregation and platelet prostaglandin biosynthesis has been assessed in a group of 11 diabetic patients with painful peripheral neuropathy. Before CSII and compared with results obtained on samples from age- and sex-matched control subjects, there was enhanced reactivity of the platelets from diabetic patients to ADP, collagen and sodium arachidonate (NaAA). There was also increased thromboxane B2 (TXB2) production after platelet stimulation by NaAA. In contrast, collagen-induced thromboxane production by platelets from diabetic patients was significantly less than that of platelets from controls. Treatment by CSII resulted in a statistically significant improvement in glycaemic control and this was maintained for the 16 week period of the study. At 16 weeks and in the presence of near-normal glycaemic control, the enhanced platelet reactivity in response to collagen and NaAA persisted and that to ADP was further increased. Collagen-induced thromboxane production was, however, corrected by CSII.

Topics: Adenosine Diphosphate; Adult; Arachidonic Acid; Arachidonic Acids; Blood Glucose; Blood Platelets; Collagen; Diabetes Mellitus, Type 1; Female; Humans; Insulin Infusion Systems; Male; Middle Aged; Platelet Aggregation; Thromboxane B2

We investigated the ability of platelets from two groups of diabetics type I and two groups of healthy volunteers matched of age to generate thromboxane B2 (TXB2) during spontaneous clotting of whole blood. The serum concentration of TXB2, reflecting the ability of the platelets to generate TXA2 during clotting, was measured by gas liquid chromatography. Platelets from old diabetics with more than 40 years duration of diabetes mellitus formed significantly less TXB2 than those from old healthy controls. Platelets from juvenile diabetics (9 years duration of disease) formed nearly the same amount of TXB2 as those from young healthy volunteers. The importance of these results is discussed.

Topics: Adult; Age Factors; Blood Coagulation; Diabetes Mellitus, Type 1; Female; Humans; Male; Middle Aged; Reference Values; Thromboxane B2; Thromboxanes

Platelets from diabetic subjects with circulating immune complexes (CIC) synthesized greater amounts of thromboxane than did platelets from CIC-negative patients or controls. In view of the known action of CIC on platelet function, a relationship between these two factors may be suggested in the initiation and progression of microangiopathy in diabetes.

Topics: Antibodies, Anti-Idiotypic; Antigen-Antibody Complex; Blood Platelets; Child; Complement C3; Diabetes Mellitus, Type 1; Female; Humans; Immunoglobulin G; Insulin Antibodies; Male; Thromboxane B2; Thromboxanes

Plasma concentrations of beta-thromboglobulin (B-TG) and of Thromboxane B2 (TxB2) were found to be increased in diabetics but their values didn't result in relation to simultaneous fasting glycemia. The aim of this study was to elucidate if the B-TG and TxB2 levels were correlated with the indexes of medium and long-term diabetes control, namely non-enzymatic glycosylation of serum proteins (GSP) and irreversibly glycosylated hemoglobin, stable (S) HbA1. Therefore the behaviour of B-TG, TxB2, glycemia, GSP, T-HbA1 (stable and labile) and S-HbA1 were determined in 37 type 1 diabetics without any apparent vascular complication. All these parameters, except S-HbA1, were studied also in 8 ketoacidotic diabetic out patients before and during the recovery of metabolic control. Glycemia was assayed by the method of Trinder; B-TG and TxB2 were determined by radio-immunoassay. GSP was measured by chemical procedure using thiobarbituric acid (TBA test). The concentration of HbA1 was performed before and after incubation of erythrocytes for 6 h at 37 degrees C in saline to evaluate T and S-HbA1. In the out-patients B-TG and TxB2 were found to be correlated only with GSP. During the recovery of glycemic control a progressive decrease in the levels of T-BG and TxB2 was observed. We conclude that in vitro platelet activation i.e. B-TG and TxB2 levels, stable metabolite of proaggregatory TxA2, are deranged in relation to medium term glycemic disturbance rather than to short-term glucose fluctuations.

Topics: Adult; Beta-Globulins; beta-Thromboglobulin; Blood Glucose; Blood Proteins; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Male; Thromboxane B2; Thromboxanes

Plasma concentrations of a stable metabolite of prostacyclin, 6-keto-prostaglandin Fla (6-keto-PGF1a), and the ability of platelets to generate thromboxane B2 (TxB2), a metabolite of thromboxane A2, during spontaneous clotting of the blood were measured in 40 diabetic children and 16 healthy controls. The diabetics' platelets generated TxB2 to a lesser extent than those of controls, whereas no difference was seen in plasma 6-keto-PGF1a concentration. The balance and duration of diabetes were not related to TxB2 or 6-Keto-PGF1a. The results do not support the theory that an absolute or relative prostacyclin deficiency could trigger the onset of diabetic vascular complications.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Blood Platelets; Child; Child, Preschool; Diabetes Mellitus, Type 1; Epoprostenol; Female; Humans; Male; Prostaglandins; Thromboxane A2; Thromboxane B2; Thromboxanes

TXB2 formation in PRP after thrombin or arachidonic acid stimulation was determined in 23 young compensated insulin-dependent diabetic patients, and in 10 control subjects of equivalent age. No significant difference in TXB2 synthesis during the times sampled was observed. Six out of 23 diabetics had circulating immune complexes (CIC) in their sera as detected by the C1q-SP; after the addition of arachidonic acid and thrombin the amount of TXB2 in PRP from CIC-positive patients was significantly higher than in PRP from CIC-negative patients. The increased synthesis of PG endoperoxides in CIC-positive patients could be a direct effect of antigen-antibody complexes on platelets.

Topics: Adolescent; Antigen-Antibody Complex; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Child; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Male; Thrombin; Thromboxane B2; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Child; Diabetes Mellitus, Type 1; Female; Humans; Male; Thromboxane B2; Thromboxanes

Topics: Adolescent; Adult; Diabetes Mellitus; Diabetes Mellitus, Type 1; Epoprostenol; Humans; Keto Acids; Male; Prostaglandins F; Thromboxane B2; Thromboxanes