thromboxane-b2 and Diabetes-Mellitus--Type-2

The abnormal metabolic state that accompanies diabetes renders arteries susceptible to atherosclerosis, being capable of altering the functional properties of multiple cell types, including endothelium and platelets. In particular, an altered platelet metabolism and changes in intraplatelet signaling pathways may contribute to the pathogenesis of atherothrombotic complications of diabetes. A variety of mechanisms may be responsible for enhanced platelet aggregation. Among them, hyperglycemia may represent a causal factor for in vivo platelet activation, and may be responsible for nonenzymatic glycation of platelet glycoproteins, causing changes in their structure and conformation, as well as alterations of membrane lipid dynamics. Furthermore, hyperglycemia-induced oxidative stress is responsible for enhanced peroxidation of arachidonic acid to form biologically active isoprostanes, which represents an important biochemical link between impaired glycemic control and persistent platelet activation. Finally, increased oxidative stress is responsible for activation of transcription factors and expression of redox-sensitive genes leading to a phenotypic switch of endothelium toward an adhesive, pro-thrombotic condition, initial platelet activation, adhesion and subsequent platelet aggregate formation. All this evidence is strengthened by the results of clinical trials documenting the beneficial effects of metabolic control on platelet function, and by the finding that aspirin treatment may even be more beneficial in diabetic than in high-risk non-diabetic patients. Attention to appropriate medical management of diabetic patients will have great impact on long-term outcome in this high-risk population.

Topics: Animals; Arachidonic Acid; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Lipid Peroxidation; Models, Biological; Oxidative Stress; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Thromboxane B2

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

The aim of this study is to examine whether postprandial (PP) triglyceride-rich lipoproteins (TGRL) secreted after a moderate fat intake would activate platelets differently according to their fatty acid (FA) composition.. In a parallel single-blind randomized trial, 30 women with type 2 diabetes are assigned a breakfast containing 20 g lipids from butter versus hazelnut-cocoa spread (HCS) rich in palm oil. Blood samples are collected at fasting and 4 h PP. FA composition of fasting and PP TGRL and their effects on the activation of platelets from healthy blood donors are assessed. Both breakfasts similarly increase plasma ApoB-48, plasma, and TGRL triglycerides (p < 0.05). TGRL mean diameter increases after both breakfasts and is greater after the butter breakfast. Both breakfasts are rich in palmitic acid, and the HCS breakfast contains 45% oleic acid. TGRL FA composition reflects the dietary FA composition. Pre-incubation of platelets with fasting and PP TGRL increases collagen-stimulated aggregation (p < 0.01 vs control). Fasting and PP TGRL similarly increase agonist-induced thromboxane B. PP TGRL from type 2 diabetic women after a palm-oil spread versus butter-based mixed meal induce similar acute in vitro platelet activation.

Topics: Aged; Aged, 80 and over; Dairy Products; Diabetes Mellitus, Type 2; Dietary Fats; Fasting; Female; Humans; Lipoproteins; Meals; Middle Aged; Platelet Activation; Platelet Aggregation; Postprandial Period; Thromboxane B2; Triglycerides

Platelets from patients with type 2 diabetes are characterised by hyperactivation and high level of oxidative stress. Docosahexaenoic acid (DHA) may have beneficial effects on platelet reactivity and redox status. We investigated whether moderate DHA supplementation, given as a triglyceride form, may correct platelet dysfunction and redox imbalance in patients with type 2 diabetes. We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (n=11 post-menopausal women with type 2 diabetes) to test the effects of 400 mg/day of DHA intake for two weeks on platelet aggregation, markers of arachidonic acid metabolism, lipid peroxidation status, and lipid composition. Each two week-period was separated from the other by a six-week washout. Daily moderate dose DHA supplementation resulted in reduced platelet aggregation induced by collagen (-46.5 %, p< 0.001), and decreased platelet thromboxane B2 (-35 %, p< 0.001), urinary 11-dehydro-thromboxane B2 (-13.2 %, p< 0.001) and F2-isoprostane levels (-19.6 %, p< 0.001) associated with a significant increase of plasma and platelet vitamin E concentrations (+20 % and +11.8 %, respectively, p< 0.001). The proportions of DHA increased both in plasma lipids and in platelet phospholipids. After placebo treatment, there was no effect on any parameters tested. Our findings support a significant beneficial effect of low intake of DHA on platelet function and a favourable role in reducing oxidative stress associated with diabetes.

Topics: Administration, Oral; alpha-Tocopherol; Antioxidants; Arachidonic Acid; Blood Platelets; Collagen; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Supplements; Dinoprost; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Double-Blind Method; F2-Isoprostanes; Fatty Acids; Female; Humans; Lipid Peroxidation; Lipids; Membrane Lipids; Middle Aged; Oxidative Stress; Phospholipids; Platelet Aggregation; Postmenopause; Thromboxane B2

The effect of acetylsalicylic acid (ASA) may be measured through the analysis of urinary concentrations of 11-dehydrothromboxane B2 (11-dhTXB2), a metabolite of thromboxane A2, which is a potent platelet aggregant agent. It has been suggested that metformin (an oral antidiabetic drug) could improve oxidative stress and control platelet activation in type 2 diabetic patients, potentially reducing cardiovascular risk. We determined the concentrations of urinary 11-dhTXB2 in type 2 diabetic patients taking ASA and its concentrations with metformin use and several other clinical variables (hypertension, age, gender, smoking, body mass index, insulin and statin use), considering a reduction of at least 75% in the concentrations of this marker as a target, compared to results before ASA intake.. Urinary concentrations of 11-dhTXB2 of 81 type 2 diabetic patients were measured before and at 15 days taking 100 mg of aspirin daily.. Most patients who presented a reduction of 11-dhTXB2 above 75% were under metformin use. This reduction was achieved in 51.5% of patients taking this drug, against 20.0% in the patients who were not (p=0.027). The analysis of the other variables did not show a significant difference. The use of metformin appears to play a role in the reduction of 11-dhTXB2 concentrations in type 2 diabetic patients.. According to previous reports, hyperglycemia control seems to be a determinant factor for the success of ASA therapy, given the influence of metformin in the reduction of 11-dhTXB2 concentrations.

Topics: Aspirin; Biological Transport; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Hypoglycemic Agents; Insulin Resistance; Intestinal Absorption; Male; Metformin; Middle Aged; Oxidative Stress; Risk Factors; Thromboxane B2

Evidence from the literature suggests diminished acetylsalicylic acid (ASA) treatment efficacy in type 2 diabetes (DM2). High on-aspirin platelet reactivity (HAPR) in DM2 has been linked to poor glycemic and lipid control. However, there are no consistent data on the association between HAPR and insulin resistance or adipose tissue metabolic activity. The aim of this study was to assess the relationship between laboratory response to ASA and metabolic control, insulin resistance and adipokines in DM2.. A total of 186 DM2 patients treated with oral antidiabetic drugs and receiving 75 mg ASA daily were included in the analysis. Response to ASA was assessed by measuring serum thromboxane B2 (TXB2) concentration and expressed as quartiles of TXB2 level. The achievement of treatment targets in terms of glycemic and lipid control, insulin resistance parameters (including Homeostatic Model Assessment-Insulin Resistance, HOMA-IR, index), and serum concentrations of high-molecular weight (HMW) adiponectin, leptin and resistin, were evaluated in all patients. Univariate and multivariate logistic regression analyses were performed to determine the predictive factors of serum TXB2 concentration above the upper quartile and above the median.. Significant trends in age, body mass index (BMI), HOMA-IR, HMW adiponectin concentration, C-reactive protein concentration and the frequency of achieving target triglyceride levels were observed across increasing quartiles of TXB2. In a multivariate analysis, only younger age and higher BMI were independent predictors of TXB2 concentration above the upper quartile, while younger age and lower HMW adiponectin concentration were predictors of TXB2 concentration above the median.. These results suggest that in DM2, the most important predictor of HAPR is younger age. Younger DM2 patients may therefore require total daily ASA doses higher than 75 mg, preferably as a twice-daily regimen, to achieve full therapeutic effect. Higher BMI and lower HMW adiponectin concentration were also associated with less potent ASA effect. This is the first study to demonstrate an association of lower adiponectin concentration with higher serum TXB2 level in patients treated with ASA.

Topics: Adiponectin; Age Factors; Aged; Aspirin; Biomarkers; Body Mass Index; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Thromboxane B2; Treatment Outcome

Diabetes mellitus type 2 (DM2) is associated with high platelet reactivity both in patients who do not receive antiplatelet drugs and in those treated with acetylsalicylic acid (ASA). The pathomechanism of this phenomenon has not been fully understood.. 1. To evaluate variability of platelet reactivity in patients with DM2 treated with oral antidiabetic drugs and receiving chronic ASA therapy. 2. To identify independent predictors of high platelet reactivity during ASA therapy in patients with DM2.. We studied 171 patients with DM2 treated with oral antidiabetic drugs and receiving long-term treatment with 75 mg of ASA daily, selected among the participants of the prospective AVOCADO study. Platelet function was simultaneously evaluated using 4 methods: 1. measurement of serum thromboxane B2 (TXB2) concentration; 2. measurement of urinary 11-dehydrothromboxane B2 (11-dhTXB2) concentration; 3. VerifyNow® automated analyser; 4. PFA-100® automated analyser.High platelet reactivity was defined as at least 3 of the following criteria: 1. serum TXB2 concentration in the upper quartile;2. urinary 11-dhTXB2 concentration in the upper quartile; 3. value ≥ 550 aspirin reaction units (ARU) by VerifyNow®;4. collagen-epinephrine closure time (CEPI-CT) below median of readings other than 300 s by PFA-100®. In all patients, DM2 control was evaluated, insulin resistance was measured using HOMA-IR, and routine laboratory tests were performed, including full blood count, renal function parameters, and inflammation markers.. Mean patient age was 67.8 years, and median duration of DM2 was 5 years. We found poor agreement between different tests of platelet function. ARU ≥ 550 (VerifyNow®) was found in 14.0% of patients, and CEPI-CT below median of readings other than 300 s (PFA-100®) was found in 32.8% of patients. Our criteria of high platelet reactivity were met by 9.9% of patients. In multivariate logistic regression analysis, independent predictors of high platelet reactivity despite ASA therapy included chronic heart failure, current smoking, and higher leukocyte count.. 1. Patients with DM2 are characterised by large variability of platelet reactivity, with little agreement between various methods. 2. Smoking, chronic heart failure, and subclinical inflammation may be associated with high platelet reactivity in patients with DM2 treated with ASA.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Biomarkers; Blood Platelet Disorders; Blood Platelets; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Logistic Models; Male; Middle Aged; Multivariate Analysis; Platelet Aggregation; Platelet Aggregation Inhibitors; Prospective Studies; Thromboxane B2

Low-dose aspirin seems to offer no benefit in the primary prevention of cardiovascular disease in type 2 diabetes mellitus (DM2). The anti-platelet effect may be diminished by poor glycemic control or inadequate dosing of aspirin.. To study the effects of both glycemic control and increasing aspirin dose on platelet response to aspirin in DM2 patients and matched controls.. Platelet effects of increasing doses of aspirin (30, 100 and 300 mg daily) were prospectively assessed in 94 DM2 patients and 25 matched controls by measuring thromboxane levels in urine (11-dhTxB2) and platelet aggregation using VerifyNow(®) and light transmission aggregometry (LTA). DM2 patients were stratified for glycemic control (hemoglobin-A1c [HbA1c] ≤ 53, 53-69, ≥ 69 mmol mol(-1)).. At baseline, median 11-dhTxB2 excretion was higher in the poorly controlled patients (77 ng mmol(-1)), and the moderately controlled (84 ng mmol(-1)) compared with the well-controlled patients (64 ng mmol(-1)) and controls (53 ng mmol(-1)), P < 0.01. Next, 30 mg of aspirin reduced 11-dhTxB2 excretion to 31, 29 and 24 ng mmol(-1) in the poorly, moderately and well-controlled patients, respectively, and to 19 ng mmol(-1) in controls, P < 0.001. VerifyNow(®) and LTA were also incompletely suppressed in DM2 patients using 30 mg of aspirin, but 100 mg resulted in similar platelet suppression in all groups, with no additional effect of 300 mg.. DM2 patients with inadequate glycemic control (HbA1c > 53 mmol mol(-1)) have higher baseline platelet activity and incomplete suppression of platelet activity with 30 mg of aspirin. However, 100 mg of aspirin leads to optimal inhibition irrespective of glycemic control, and 300 mg does not further improve platelet suppression.

Topics: Adult; Aged; Aspirin; Biomarkers; Blood Platelets; Cardiovascular Diseases; Chi-Square Distribution; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Multivariate Analysis; Netherlands; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Regression Analysis; Thromboxane B2; Treatment Outcome

Interindividual variability in response to aspirin has been popularized as 'resistance'. We hypothesized that faster recovery of platelet cyclooxygenase-1 activity may explain incomplete thromboxane (TX) inhibition during the 24-h dosing interval.. To characterize the kinetics and determinants of platelet cyclooxygenase-1 recovery in aspirin-treated diabetic and non-diabetic patients.. One hundred type 2 diabetic and 73 non-diabetic patients on chronic aspirin 100 mg daily were studied. Serum TXB(2) was measured every 3 h, between 12 and 24 h after a witnessed aspirin intake, to characterize the kinetics of platelet cyclooxygenase-1 recovery. Patients with the fastest TXB(2) recovery were randomized to aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily, for 28 days and TXB(2) recovery was reassessed.. Platelet TXB(2) production was profoundly suppressed at 12 h in both groups. Serum TXB(2) recovered linearly, with a large interindividual variability in slope. Diabetic patients in the third tertile of recovery slopes (≥ 0.10 ng mL(-1) h(-1) ) showed significantly higher mean platelet volume and body mass index, and younger age. Higher body weight was the only independent predictor of a faster recovery in non-diabetics. Aspirin 100 mg twice daily completely reversed the abnormal TXB(2) recovery in both groups. Interindividual variability in the recovery of platelet cyclooxygenase activity during the dosing interval may limit the duration of the antiplatelet effect of low-dose aspirin in patients with and without diabetes. Inadequate thromboxane inhibition can be easily measured and corrected by a twice daily regimen.

Topics: Aged; Aspirin; Blood Platelets; Case-Control Studies; Cyclooxygenase 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Humans; Male; Thromboxane B2

Aspirin (ASA) irreversibly inhibits platelet cyclooxygenase-1 (COX-1) leading to decreased thromboxane-mediated platelet activation. The effect of ASA ingestion on platelet activation, thromboxane generation, oxidative stress and anti-oxidant biomarkers was studied in type 2 diabetes mellitus (DM).. Baseline and post-ASA samples (100/325 mg x 7 days) were obtained from 75 DM patients and 86 healthy controls for urinary 11-dehydro-thromboxane B2 (11 dhTxB2), 8-iso-prostaglandin-F2α (8-isoPGF2α) and serum sP-Selectin, nitrite (NO(2)(-)), nitrate (NO(3)(-)) and paraoxonase 1 (PON1) activity.. Compared to baseline controls, baseline DM had higher mean levels of 11 dhTxB2 (3,665 ± 2,465 vs 2,450 ± 1,572 pg/mg creatinine, p=0.002), 8-isoPGF2α (1,457 ± 543 vs 1,009 ± 412 pg/mg creatinine, p<0.0001), NO(2)(-) (11.8 ± 7.3 vs 4.8 ± 5.3 μM, p<0.0001), NO(3)(-) (50.4 ± 39.3 vs 20.9 ± 16.7 μM, p<0.0001) and sP-Selectin (120.8 ± 56.7 vs 93.0 ± 26.1 ng/mL, p=0.02), and the same held for post-ASA levels (p<0.0001). ASA demonstrated no effect on 8-isoPGF2α, NO(2)(-), NO(3)(-), sP-Selectin or PON1 activity in either DM or controls. Post ASA inhibition of urinary 11 dhTxB2 was 71.5% in DM and 75.1% in controls. There were twice as many ASA poor responders in DM than in controls (14.8% and 8.4%) based on systemic thromboxane reduction. Urinary 8-isoPGF2α excretion was greater in DM ASA poor responders than good responders (p<0.009).. This suggests that oxidative stress may maintain platelet function irrespective of COX-1 pathway inhibition and/or increase systemic generation of thromboxane from non-platelet sources.

Topics: Administration, Oral; Antioxidants; Aspirin; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Oxidative Stress; Thromboxane B2

Patients with type 2 diabetes mellitus (T2DM) have reduced aspirin-induced pharmacodynamic effects. This may be attributed to increased platelet turnover rates resulting in an increased proportion of non-aspirin-inhibited platelets during the daily dosing interval. The hypothesis of this study was that an increase in the frequency of drug administration [twice daily (bid) versus once daily (od)] may provide more effective platelet inhibition in T2DM patients.. T2DM patients with stable coronary artery disease were prospectively recruited. Patients modified their aspirin regimen on a weekly basis according to the following scheme: 81 mg/od, 81 mg/bid, 162 mg/od, 162 mg/bid, and 325 mg/od. Pharmacodynamic assessments included light-transmittance aggregometry after arachidonic acid, collagen and adenosine diphosphate stimuli; VerifyNow-Aspirin assay; and serum thromboxane B(2) (TXB(2)) levels. Twenty patients were analyzed. All patients were sensitive and compliant to aspirin irrespective of dose, as assessed by arachidonic acid-induced aggregation. When aspirin was administered once daily, there was no significant effect on platelet reactivity by increasing the once-daily dosing using aspirin-sensitive assays (collagen-induced aggregation and VerifyNow-Aspirin). An increase in aspirin dose by means of a second daily administration was associated with a significant reduction in platelet reactivity assessed by collagen-induced aggregation and VerifyNow-Aspirin between 81 mg/od and 81 mg/bid (P<0.05 for both assays) and between 81 mg/od and 162 mg/bid (P<0.05 for both assays). There was no impact of aspirin dosing regimens on adenosine diphosphate-induced aggregation. A dose-dependent effect of aspirin was observed on serum TXB(2) levels (P=0.003).. Aspirin dosing regimens are associated with different pharmacodynamic effects in platelets from T2DM patients and stable coronary artery disease, with a twice-daily, low-dose aspirin administration resulting in greater platelet inhibition than once-daily administration as assessed by aspirin-sensitive assays and a dose-dependent effect on serum TXB(2) levels. The clinical implications of a modified aspirin regimen tailored to T2DM patients warrant further investigation.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01201785.

Topics: Aged; Aspirin; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Prospective Studies; Thromboxane B2

Aspirin is widely used in the secondary prevention of coronary artery diseases, including myocardial infarction, stroke, and vascular related deaths. However, the antiplatelet effect of aspirin appears to be variable and aspirin resistance (AR) is currently still controversial for Chinese patients. The aim of this study was to describe the prevalence of AR, and identify possible risk factors associated with a lack of response to aspirin treatments in patients with unstable coronary artery disease.. Platelet function tests with arachidonic acid (ARA) and urinary 11-dehydro-thromboxane B2 (11-DH-TXB2) concentrations were performed in 262 patients with unstable coronary artery disease who had not been taking aspirin before admission. ARA induced platelet aggregation and 11-DH-TXB2 were detected to evaluate the functional and biochemical responses to aspirin before and on days 1, 4, and 10 after aspirin administration. Six-month follow-up was completed in patients who developed AR to evaluate the effect of aspirin in a long-term treatment. GP1Bα (C1018T), Pl (A1/A2), P2Y1 (A1622G), TBXA2R (T924C) were also detected to evaluate the influence of genetic variant on aspirin responsiveness.. A total of 8.8% of patients were indentified as AR at the first day after aspirin treatment. The level of urine 11-DH-TXB2 in the AR group was higher compared to non-AR group (P < 0.05). There was no relationship between ARA induced platelet aggregation and urinary 11-DH-TXB2 levels (r = 0.038, P = 0.412). The results of DNA sequencing showed that TBXA2R-924TT homozygotes had a significantly high rate of AR. Logistic regression demonstrated that diabetes was an independent risk factor of AR.. In the beginning period of administration, aspirin was not a sufficient factor that inhibits platelet aggregation. TBXA2R-924T allele was involved in AR. Diabetes was an independent risk factor of AR.

Topics: Aged; Aged, 80 and over; Arachidonic Acid; Aspirin; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Genotype; Humans; Male; Membrane Glycoproteins; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Platelet Glycoprotein GPIb-IX Complex; Polymerase Chain Reaction; Polymorphism, Genetic; Receptors, Purinergic P2Y1; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane B2

The efficacy of low-dose aspirin in type 2 diabetes mellitus (T2DM) has been questioned. We tested if twice daily dosing of aspirin would be more effective in T2DM, possibly due to increased platelet turnover. A randomised cross-over study compared 75 mg aspirin OD, 75 mg BID and 320 mg OD (≥ 2 week treatment periods) in 25 patients with T2DM and micro- or macrovascular complications. Platelet responses were examined by impedance aggregometry (WBA) and the IMPACT-R aspirin test in whole blood, light transmittance aggregometry in platelet-rich plasma (LTA), and urinary 11-dehydro-thromboxane B2 (TxM). Aspirin 75 mg BID decreased arachidonic acid (AA)-induced WBA compared to 75 mg OD (9.7 ± 4.5 vs. 12.6 ± 3.5 ohm; p = 0.003) or to 320 mg OD (11.5 ± 4.2 Ohms; p = 0.049). WBA responses to collagen were similarly attenuated by BID or high dosing (by 12-14%; p = 0.02 for both). The IMPACT-R showed a better response to 75 mg BID compared to 75 mg OD (p = 0.049), but not to 320 mg OD. AA-induced aggregation by LTA was <6.5% on all occasions, with no differences between aspirin dosages. TxM was reduced after 320 mg OD (p = 0.002), but not 75 mg BID (p = 0.07). Reticulated platelets were highly correlated with mean platelet volume (MPV; r2 = 0.74, p<0.0001). Both markers for platelet turnover were correlated with AA-induced WBA, but neither identified patients who benefited from BID dosing dependably. In conclusion, twice daily dosing improved laboratory responses to aspirin in high risk T2DM patients. Studies of whether BID dosing of aspirin can improve clinical outcomes in such patients are of interest.

Topics: Aspirin; Blood Platelets; Cells, Cultured; Clinical Protocols; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Dosage Calculations; Humans; Microvessels; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane B2

Chronic hyperglycemia is a major contributor to in vivo platelet activation in diabetes mellitus.. To evaluate the effects of acarbose, an alpha-glucosidase inhibitor, on platelet activation and its determinants in newly diagnosed type 2 diabetic patients.. Forty-eight subjects (26 males, aged 61 +/- 8 years) with early type 2 diabetes (baseline hemoglobin A(1c) < or = 7% and no previous hypoglycemic treatment) were randomly assigned to acarbose up to 100 mg three times a day or placebo, and evaluated every 4 weeks for 20 weeks. The main outcome measures were urinary 11-dehydro-thromboxane (TX)B(2) (marker of in vivo platelet activation) and 8-iso-prostaglandin (PG)F(2alpha) (marker of in vivo lipid peroxidation) excretion rate, 2-h postprandial plasma glucose (PPG) after a test meal, and assessment of glucose fluctuations by mean amplitude of glycemic excursions (MAGE).. Baseline measurements revealed biochemical evidence of enhanced lipid peroxidation and platelet activation. As compared with the placebo group, patients treated with acarbose had statistically significant reductions in urinary 11-dehydro-TXB(2) and 8-iso-PGF(2alpha) excretion rate as early as after 8 weeks and at each subsequent time point (between-group P < 0.0001 at 12, 16 and 20 weeks), following earlier decreases in PPG and MAGE. Multiple regression analyses in the acarbose group revealed that PPG was the only significant predictor of 11-dehydro-TXB(2) urinary excretion rate (beta = 0.39, P = 0.002) and MAGE the only predictor of 8-iso-PGF(2alpha) urinary excretion rate (beta = 0.42, P = 0.001).. Postprandial hyperglycemia is associated with enhanced lipid peroxidation and platelet activation in early type 2 diabetes. A moderate decrease in PPG achieved with acarbose causes time-dependent downregulation of these phenomena, suggesting a causal link between early metabolic abnormalities and platelet activation in this setting.

Topics: Acarbose; Aged; Arginine; Biomarkers; Blood Glucose; C-Reactive Protein; CD40 Ligand; Diabetes Mellitus, Type 2; Dinoprost; Double-Blind Method; Enzyme Inhibitors; Female; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Italy; Lipid Peroxidation; Male; Middle Aged; P-Selectin; Platelet Activation; Postprandial Period; Thromboxane B2; Time Factors; Treatment Outcome

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

The goals of this study were to characterize the platelet contribution to soluble CD40 ligand (sCD40L), to correlate its formation with the extent of oxidative stress and platelet activation, and to investigate the effects of improved metabolic control and low-dose aspirin on these processes.. Inflammation, oxidative stress, and platelet activation are involved in the pathogenesis of type 2 diabetes (T2DM) and its complications. The CD40-CD40L interactions result in inflammatory and pro-thrombotic responses.. Urinary 8-iso-prostaglandin (PG)F2alpha and 11-dehydro-thromboxane (TX)B2, in vivo markers of oxidative stress and platelet activation, respectively, plasma CD40L, and C-reactive protein (CRP) were measured in 114 T2DM patients and 114 control patients. A randomized, parallel group, 17-day study of aspirin (30, 100, or 325 mg/day) was performed in 18 T2DM patients. A similar study was performed in six healthy volunteers (aspirin, 100 mg/day). Twenty poorly controlled T2DM patients were studied before and after improved metabolic control.. Compared with control patients, diabetic patients showed significantly higher levels of 8-iso-PGF2alpha, 11-dehydro-TXB2, sCD40L, and CRP. On multiple regression analysis, 11-dehydro-TXB2 and 8-iso-PGF2alpha excretion rates predicted sCD40L levels. Soluble CD40L linearly correlated with 11-dehydro-TXB2 (rho = 0.67, p < 0.0001), and both were reduced after one week of aspirin (p < 0.0026), with slow recovery over 10 days after aspirin withdrawal. Improved metabolic control was associated with a reduction in sCD40L, 8-iso-PGF2alpha, and 11-dehydro-TXB2.. This study provides several lines of evidence for the dependence of sCD40L release on TXA(2)-dependent platelet activation in T2DM and provides novel mechanistic insight into the amplification loops of persistent platelet activation in this setting.

Topics: Aged; Aspirin; CD40 Ligand; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dinoprost; Female; Humans; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Platelet Activation; Platelet Aggregation Inhibitors; Radioimmunoassay; Thromboxane A2; Thromboxane B2

Triflusal is an antiplatelet drug related to aspirin, with different pharmacological properties and a lower haemorrhagic risk. We aimed at comparing their effects on platelet and endothelial activation in type 2 diabetes mellitus (T2DM). In a randomized, double-blind, parallel group study, we compared the effects of three daily regimens (300, 600, and 900 mg) of triflusal, and aspirin (100mg/day) on urinary 11-dehydro-thromboxane (TX)B(2), index of in vivo platelet activation, ex vivo platelet function using the analyzer PFA-100, plasma von Willebrand factor (vWF), P-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and serum nitrite and nitrate (NO(2)(-)+NO(3)(-)) in 60 T2DM patients. Triflusal induced a dose-dependent reduction in 11-dehydro-TXB(2) and a prolongation of closure time in the presence of collagen plus epinephrine (Coll/Epi-CT). The effects of the highest triflusal dose were not different from those of aspirin. The closure time in the presence of collagen plus ADP (Coll/ADP-CT), ICAM-1, VCAM-1, and NO(2)(-)+NO(3)(-) were not modified either by triflusal or aspirin. Plasma P-selectin and vWF were reduced by triflusal but not by aspirin. In T2DM triflusal causes a profound inhibition of platelet TXA(2) biosynthesis in vivo, acting on different targets involved in the platelet-endothelial cell interactions.

Topics: Adult; Aged; Aspirin; Biomarkers; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; P-Selectin; Platelet Activation; Platelet Aggregation Inhibitors; Radioimmunoassay; Retrospective Studies; Salicylates; Thromboxane B2; von Willebrand Factor

Picotamide both inhibits thromboxane synthetase and acts as a thromboxane antagonist at the receptor level. We investigated the long-term effect of picotamide on urinary albumin excretion (UAE) at rest and induced by exercise in 30 type 2 diabetic patients who were normotensive and had microalbuminuria while at rest. The subjects of our study had a mean age of 52.5 +/- 1.6 years, BMI of 28.5 +/- 0.7 kg/m2, diabetes duration of 9.1 +/- 1.8 years, and HbA1c of 7.0 +/- 0.8%. The study was a randomized double-blind placebo-controlled trial. The patients were randomly allocated to receive for 1 year either picotamide, 300 mg, 3 tablets/day, or placebo, 3 tablets/day. The patients were asked to visit our outpatient clinic after 1, 3, 6, 9, and 12 months of treatment. At all times, blood pressure, microalbuminuria at rest, blood glucose, serum creatinine, serum picotamide, and creatinine clearance were measured; at baseline and after 6 and 12 months, all patients underwent submaximal physical exercise. After 6 months of picotamide, baseline and exercise-induced microalbuminuria were significantly decreased (up to one-third) as compared with the baseline and placebo level, with no further drops at month 12 of picotamide treatment. On placebo treatment, UAE at rest and after exercise was slightly increased compared with baseline values. The effects of picotamide occurred without significant side effects or changes in either blood pressure levels or glycometabolic control. Our study is the first long-term intervention trial in type 2 diabetes showing that an antithromboxane agent is able to decrease microalbuminuria, which in this disease is a dual marker of macro- and microangiopathy. Our findings suggest an important role for thromboxane in the pathophysiology of microalbuminuria in diabetes; moreover, we hypothesize that antithromboxane agents may have a place in the treatment/prevention of both macro- and microvascular complications in type 2 diabetic patients.

Topics: Administration, Oral; Albuminuria; Blood Pressure; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Exercise; Female; Follow-Up Studies; Heart Rate; Humans; Male; Middle Aged; Phthalic Acids; Platelet Aggregation Inhibitors; Thromboxane B2; Time Factors

Previous studies relating increased thromboxane (TX) biosynthesis to cardiovascular risk factors do not answer the question whether platelet activation is merely a consequence of more prevalent atherosclerotic lesions or reflects the influence of metabolic and hemodynamic disturbances on platelet biochemistry and function.. We examined 64 patients with large-vessel peripheral arterial disease and 64 age- and sex-matched control subjects. TXA2 biosynthesis was investigated in relation to cardiovascular risk factors by repeated measurements of the urinary excretion of its major enzymatic metabolite, 11-dehydro-TXB2, by radioimmunoassay. Urinary 11-dehydro-TXB2 was significantly (P = .0001) higher in patients with peripheral arterial disease (57 +/- 26 ng/h) than in control subjects (26 +/- 7 ng/h). Seventy percent of patients had metabolite excretion > 2 SD above the normal mean. However, 11-dehydro-TXB2 excretion was enhanced only in association with cardiovascular risk factors. Multivariate analysis showed that diabetes, hypercholesterolemia, and hypertension were independently related to 11-dehydro-TXB2 excretion. During a median follow-up of 48 months, 8 patients experienced major vascular events. These patients had significantly (P = .001) higher 11-dehydro-TXB2 excretion at baseline than patients who remained event free.. The occurrence of large-vessel peripheral arterial disease per se is not a trigger of platelet activation in vivo. Rather, the rate of TXA2 biosynthesis appears to reflect the influence of coexisting disorders such as diabetes mellitus, hypercholesterolemia, and hypertension on platelet biochemistry and function. Enhanced TXA2 biosynthesis may represent a common link between such diverse risk factors and the thrombotic complications of peripheral arterial disease.

Topics: Adult; Aged; Aspirin; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Multivariate Analysis; Platelet Activation; Prospective Studies; Reproducibility of Results; Risk Factors; Smoking; Thromboxane A2; Thromboxane B2; Vascular Diseases

We have previously shown that tight metabolic control by insulin therapy reduced thromboxane-dependent platelet activation in non-insulin-dependent diabetes mellitus (NIDDM) patients. The present study was undertaken to determine whether a similar effect could be obtained without switching diabetics in secondary failure to insulin treatment. For this purpose, we gave strict diet and exercise advise program and adjusted on a weekly basis the oral antidiabetic therapy (glipizide) that 26 patients with NIDDM had been given over the previous months. Basal measurements of urinary 11-dehydro-TXB2 and PAI-1 confirmed previous findings of enhanced levels of these parameters in NIDDM patients with macrovascular disease in comparison to age- and sex-matched controls. After 2-6 weeks, 16 patients achieved tight metabolic control associated with significant reduction of both thromboxane biosynthesis and PAI-1 levels; 10 patients remained in poor control and no significant decrease of both parameters was observed. We conclude that reduction of in-vivo platelet activation and PAI-1 antigen levels after metabolic improvement obtained by frequent reassessment of sulphonylurea therapy together with strict diet and exercise programs may have beneficial effects on the progression of diabetic micro- and macrovascular disease.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Female; Glipizide; Humans; Hypoglycemic Agents; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Thromboxane B2

To study the effects of Chinese herbal medicine Tangshenkang (TSK) capsule on diabetic nephropathy (DN), 57 patients with DN were randomly divided into two groups, the treated group and the control group, they were treated with TSK capsule and the conventional therapy respectively. There were serious disorders of metabolism in DN patients, that showed the TXB 2/6-keto-PGF1 alpha ratios and lipid peroxidase (LPO) levels were higher than that of healthy people. After 6 weeks treated with TSK capsule the albuminuria levels reduced obviously (decreased 51%), renal plasma flow (RPF) increased, glomerular filtration rate and the LPO levels decreased and a positive correlation was observed between albuminuria levels and TXB 2/6-keto-PGF1 alpha ratios while the clearance rate of creafinin didn't improve significantly. There were no significant difference in the above-mentioned parameters in the control group before and after treatment. These results suggested that TSK capsule possessed a significant effect in improving albuminuria and glomerular function. And the effect of TSK might be due to its adjusting TXB 2/6-keto-PGF1 alpha ratios and its lipid-peroxidation in DN patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drugs, Chinese Herbal; Female; Humans; Lipid Peroxides; Male; Middle Aged; Qi; Thromboxane B2

We studied 27 non-insulin-dependent diabetics without apparent atherosclerosis (AS) to investigate whether abnormal platelet function is related to asymptomatic atherosclerosis in diabetes mellitus. The degree of AS was quantitatively evaluated by determining the intimal plus medial thickness (IMT) of the carotid artery wall with ultrasound high-resolution B-mode imaging. Based on our previous finding that the upper threshold of the IMT was 1.1 mm in healthy subjects, the patients were divided into the AS-positive group with the IMT > 1.1 mm, (n = 17) and the AS-negative group with the IMT < 1.1 mm (n = 10). Among five variables measured as the factors concerned with thrombogenesis, only plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) were significantly higher in the AS-positive group than in the AS-negative group. Chronic administration of pentoxifylline (300 mg/day) significantly reduced the abnormally high plasma levels of beta-TG and PF4 in 7 patients of the AS-positive group to normal levels, without lowering the normal plasma beta-TG and PF4 levels in the remaining 10 patients. Pentoxifylline treatment did not affect the plasma levels of the 3 other variables, von Willebrand factor, 6-keto prostaglandin F1 alpha and thromboxane B2. This study suggests that the progress of atherosclerosis in diabetes mellitus is associated with in vivo platelet activation and platelet activation does not occur in diabetics without carotid atherosclerosis. Pentoxifylline may impede the vicious cycle in which atherosclerosis is accelerated by platelet activation.

Topics: Aged; Arteriosclerosis; beta-Thromboglobulin; Blood Pressure; Carotid Arteries; Carotid Artery Diseases; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Pentoxifylline; Platelet Activation; Platelet Factor 4; Prostaglandins F; Thromboxane B2; Triglycerides; Ultrasonography; von Willebrand Factor

To study the effects of a low dose of omega-3 fatty acids on platelet function and other cardiovascular risk factors in patients with non-insulin-dependent diabetes mellitus (NIDDM).. We performed a randomized, prospective, double-blind, controlled study of a low dose of omega-3 fatty acids (2.5 g/day) in 20 ambulatory subjects with NIDDM. Subjects ingested five 1-g fish oil capsules each containing 0.5 g omega-3 fatty acids or five 1-g safflower oil capsules per day for 6 weeks followed by a 6-week washout period.. Nine subjects completed the study in each group. Both groups exhibited moderate control of glucose levels; modest elevations in baseline total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels; and normal blood pressure values. In the fish oil group, plasma omega-3 fatty acid levels increased significantly. Fish oil significantly reduced the slope of the dose-response curves for collagen-induced platelet aggregation to one-third the value observed with safflower oil. No difference was observed in collagen-induced production of thromboxane A2 (TXA2, measured as the stable derivative TXB2), or in adenosine-5'-diphosphate- (ADP) induced platelet aggregation or TXA2 generation. Patients with high initial collagen-induced platelet TXA2 production showed a significantly larger drop after fish oil than safflower oil. Fish oil significantly reduced TG levels by 44 mg/dl and decreased upright systolic blood pressure (sBP) by 8 mmHg compared with safflower oil. Fish oil caused a significant but small increase in HbA1c (0.56%) and total cholesterol (20 mg/dl) but had no effect on fasting glucose, high-density lipoprotein cholesterol, or LDL-cholesterol levels.. Small doses of fish oil inhibit platelet aggregation and TXA2 production, reduce upright sBP and TG levels, and have only a small effect on glucose and cholesterol levels in patients with moderately controlled NIDDM. Small quantities of omega-3 fatty acids or dietary fish are safe and potentially beneficial in NIDDM patients.

Topics: Adult; Aged; Blood Platelets; Blood Pressure; Body Weight; Cardiovascular Diseases; Cholesterol; Diabetes Mellitus, Type 2; Dietary Fats; Double-Blind Method; Energy Intake; Fatty Acids, Omega-3; Fish Oils; Glycated Hemoglobin; Humans; Middle Aged; Platelet Aggregation; Posture; Prospective Studies; Risk Factors; Safflower Oil; Thromboxane B2; Time Factors

The aim of this study was to evaluate the effects of a fish oil preparation (MaxEPA) on hemostatic function and fasting lipid and glucose levels in non-insulin-dependent diabetic (NIDDM) subjects. Eighty NIDDM outpatients aged 55.9 yr (mean SD 11.5 yr) participated in a prospective double-blind placebo-controlled study of MaxEPA capsules (10 g/day) or olive oil (control) treatment over 6 wk. Patients received either MaxEPA or olive oil in addition to preexisting therapy. Metabolic and hemostatic variables were measured before treatment and after 3 and 6 wk. Platelet membrane eicosapentaenoic acid (EPA) content increased in the treatment group (P less than 0.001). MaxEPA supplementation was associated with a significant fall in total triglycerides (P less than 0.001) but did not affect total cholesterol (P = 0.7) compared with control treatment. Fasting plasma glucose increased after 3 wk (P = 0.01) but not after 6 wk (P = 0.17) treatment with MaxEPA. Spontaneous platelet aggregation in whole blood fell in the MaxEPA group (P less than 0.02) after 6 wk, but there were no changes in agonist-induced platelet aggregation, thromboxane generation in platelet-rich plasma, or plasma beta-thromboglobulin and platelet factor IV levels. An increase in clotting factor VII (P = 0.02), without changes in fibrinogen or factor X levels, occurred in the MaxEPA group. Similar reductions in blood pressure were observed in both groups. Dietary supplementation with MaxEPA capsules (10 g/day) in NIDDM subjects is associated with improvement in hypertriglyceridemia but with deleterious effects in factor VII and blood glucose levels. Most indices of platelet function are unaffected by this therapy.

Topics: Blood Glucose; Cardiovascular Diseases; Cholesterol; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, Diabetic; Docosahexaenoic Acids; Drug Combinations; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Female; Fish Oils; Food, Fortified; Hemostasis; Humans; Lipids; Male; Thromboxane B2; Triglycerides

Levels of immunoreactive 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) and thromboxane B2 (TXB2) were measured in peripheral venous plasma in a group of volunteers and non-insulin dependent diabetic patients (NIDDS). Levels of these eicosanoids were close to the limit of sensitivity of the radioimmunoassays and consequently data are reported as maximal values. Basal plasma levels of 6-oxo-PGF1 alpha did not exceed 5 pg/ml in either group and maximal levels of immunoreactive TXB2 were 125 +/- 14 and 128 +/- 8 pg/ml for volunteers and NIDDS respectively. Attempts to elicit peripheral vascular prostacyclin biosynthesis in volunteers by using forearm ischaemia produced no increase in plasma 6-oxo-PGF1 alpha levels. Measurement of the combined plasma levels of 6-oxo-PGF1 alpha, 13,14-dihydro-6-oxo-PGF1 alpha, 13,14-dihydro-6,15-dioxo-PGF1 alpha and 6-oxo-PGE1 indicated that these were also low (less than 5 pg/ml) and that failure to demonstrate increased 6-oxo-PGF1 alpha levels was unlikely to have arisen from metabolism of prostacyclin to one or more of these metabolites. Measurement of 6-oxo-PGF1 alpha and TXB2 in peripheral venous plasma before and during chloropropamide alcohol flushing (CPAF) did not provide evidence for a role for these eicosanoids in the etiology of this phenomenon. These findings point to the need for a reappraisal of studies that have described altered plasma levels of 6-oxo-PGF1 alpha and TXB2 in CPAF and other pathophysiological conditions in man.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Chlorpropamide; Diabetes Mellitus, Type 2; Ethanol; Female; Flushing; Forearm; Humans; Indomethacin; Ischemia; Male; Middle Aged; Radioimmunoassay; Thromboxane B2; Thromboxanes

Cardiovascular disease is a leading cause of mortality among patients with type 2 diabetes mellitus (T2DM). Numerous patients with T2DM show resistance to aspirin treatment, which may explain the higher rate of major adverse cardiovascular events observed compared with non-diabetes patients, and it has recently been shown that aspirin resistance is mainly related to accelerated platelet turnover with persistent high platelet reactivity (HPR) 24h after last aspirin intake. The mechanism behind HPR is unknown. The aim of this study was to investigate the precise rate and mechanisms associated with HPR in a population of T2DM patients treated with aspirin.. Included were 116 consecutive stable T2DM patients who had attended our hospital for their yearly check-up. HPR was assessed 24h after aspirin intake using light transmission aggregometry (LTA) with arachidonic acid (AA) and serum thromboxane B2 (TXB2) measurement. Its relationship with diabetes status, insulin resistance, inflammatory markers and coronary artery disease (CAD) severity, using calcium scores, were investigated.. Using LTA, HPR was found in 27 (23%) patients. There was no significant difference in mean age, gender ratio or cardiovascular risk factors in patients with or without HPR. HPR was significantly related to duration of diabetes and higher fasting glucose levels (but not consistently with HbA. Our results reveal that 'aspirin resistance' is frequently found in T2DM, and is strongly related to insulin resistance and severity of CAD, but weakly related to HbA

Topics: Aged; Arachidonic Acid; Aspirin; C-Reactive Protein; Coronary Artery Disease; Diabetes Mellitus, Type 2; Drug Resistance; Female; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation; Insulin Resistance; Interleukin-10; Interleukin-6; Male; Middle Aged; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Severity of Illness Index; Thrombopoietin; Thromboxane B2; Tumor Necrosis Factor-alpha; Vascular Calcification

Antiplatelet therapy resistance against acetylsalicylic acid (ASA) and/or clopidogrel in coronary heart disease (CHD) is common with diabetes mellitus. One factor might involve platelet receptor ITGB3 gene polymorphism. We aimed to assess resistance together with platelet reactivity parameters, the polymorphism, plus diabetes type 2 coexistence. The study included 185 patients with CHD, including 58 diabetics, aged 62.3 ± 8.2 years. Patients were treated long-term with ASA, plus clopidogrel, both 75 mg/d. Platelet aggregation was measured with arachidonic acid (ASPI test; ASA-response assessment) or ADP (ADP test; clopidogrel-response assessment). Thromboxane B2 (TXB2) and fibrinogen concentrations were measured and ITGB3 PIA1>A2 variants identified. Increases in PLT, glucose and SBP were demonstrated with dual resistance or to clopidogrel. Regardless of response, diabetics (versus non-diabetics) had elevated platelet aggregation with the ADP test (P = 0.0198), higher TXB2 (P = 0.0501), BMI (P = 0.0003) and SBP (P = 0.0627). ITGB3 PIA1/A1 homozygotes had higher platelet aggregation with the ASPI test (P = 0.0513), and fibrinogen concentrations (P = 0.0133), relative to A2 allele carriers. Significant associations of diabetes with clopidogrel resistance (P = 0.0011) and PIA1/A1 homozygotes with ASA resistance (P = 0.0518) were found. Higher concentrations of TXB2 (P = 0.0223) and higher SBP (P = 0.0063) were found with diabetes (versus non-diabetic) in PIA1/A1 homozygotes. We concluded that diabetes with CHD weakens response to antiplatelet drugs, especially to clopidogrel; and hyperglycaemia, hypertension and obesity might also play an important role. Diabetics' resistance to ASA is associated with increased platelet reactivity, perhaps related to the more frequent ITGB3 PIA1 allele and increased TXB2 generation. The PIA1 allele may be a potential factor for aspirin resistance with elevated fibrinogen concentration.

Topics: Blood Platelets; Clopidogrel; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Fibrinogen; Humans; Integrin beta3; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Platelet Glycoprotein GPIIb-IIIa Complex; Polymorphism, Genetic; Prospective Studies; Thromboxane B2

Previous studies have suggested less cardioprotective benefit of aspirin in adults with diabetes, raising concerns about "aspirin resistance" and potentially reduced effectiveness for prevention of cardiovascular disease (CVD).. To examine differences in platelet response to aspirin by diabetes status.. We examined platelet response before and after aspirin (81 mg/day for 14 days) in 2113 adults (175 with diabetes, 1,938 without diabetes), in the Genetic Study of Aspirin Responsiveness cohort, who had family history of early-onset CVD.. In vivo platelet activation (urinary thromboxane B2), in vitro platelet aggregation to agonists (arachidonic acid, adenosine diphosphate, collagen), and platelet function analyzer-100 closure time.. Although adults with diabetes had higher in vivo platelet activation before aspirin, the reduction in in vivo platelet activation after aspirin was similar in those with vs without diabetes. Likewise, the reduction in multiple in vitro platelet measures was similar after aspirin by diabetes status. In regression analyses adjusted for age, sex, race, BMI, smoking, platelet counts, and fibrinogen levels, in vivo platelet activation remained higher in adults with vs without diabetes after aspirin (P = 0.04), but this difference was attenuated after additional adjustment for preaspirin levels (P = 0.10). No differences by diabetes status were noted for any of the in vitro platelet measures after aspirin in fully adjusted models that also accounted for preaspirin levels.. In vitro platelet response to aspirin does not differ by diabetes status, suggesting no intrinsic differences in platelet response to aspirin. Instead, factors extrinsic to platelet function should be investigated to give further insights into aspirin use for primary prevention in diabetes.

Topics: Adult; Aspirin; Blood Platelets; Coronary Artery Disease; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Thromboxane B2; Treatment Outcome

Topics: Aspirin; Diabetes Mellitus, Type 2; Humans; Obesity; Platelet Aggregation Inhibitors; Thromboxane B2

Increased particulate matter (PM) air pollutant concentrations have been associated with platelet activation. It was postulated that elevated air pollutant concentrations would be associated with increases in measures of platelet function and that responses would be blunted when taking aspirin and/or fish oil. Data from a sequential therapy trial (30 subjects with type 2 diabetes mellitus), with 4 clinic visits (first: no supplements, second: aspirin, third: omega-3 fatty acid supplements, fourth: aspirin and omega-3 fatty acids) per subject, were utilized. Using linear mixed models, adjusted for relative humidity, temperature, visit number, and season, changes in three platelet function measures including (1) aggregation induced by adenosine diphosphate (ADP), (2) aggregation induced by collagen, and (3) thromboxane B2 production were associated with interquartile range (IQR) increases in mean concentrations of ambient PM2.5, black carbon, ultrafine particles (UFP; 10-100 nm), and accumulation mode particles (AMP; 100-500 nm) in the previous 1-96 h. IQR increases in mean UFP and AMP concentrations were associated with significant decreases in platelet response, with the largest being a -0.43 log(pg/ml) decrease in log(thromboxane B2) (95% CI = -0.8, -0.1) associated with each 582-particles/cm(3) increase in AMP, and a -1.7 ohm reduction in collagen-induced aggregation (95% CI = -3.1, -0.3) associated with each 2097-particles/cm(3) increase in UFP in the previous 72 h. This UFP effect on thromboxane B2 was significantly muted in diabetic subjects taking aspirin (-0.01 log[pg/ml]; 95% CI = -0.4, 0.3). The reason for this finding remains unknown, and needs to be investigated in future studies.

Topics: Adult; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Aspirin; Blood Platelets; Collagen; Diabetes Mellitus, Type 2; Fatty Acids, Omega-3; Female; Humans; Male; Middle Aged; Particle Size; Particulate Matter; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Thromboxane B2; Weather

Reduced antiplatelet effect of aspirin has been reported in patients with type 2 diabetes, and recent studies suggest that once-daily aspirin provides insufficient platelet inhibition. We investigated if the effect of aspirin declined during the 24-hour dosing interval in patients with coronary artery disease and type 2 diabetes, and whether this correlated with increased platelet turnover. Furthermore, the intra-individual variation in platelet aggregation was determined during a 28-day period. We included 47 patients with coronary artery disease and type 2 diabetes treated with aspirin 75 mg daily. Blood samples were obtained 1 and 24 hours after aspirin intake, and this was repeated three times with a 2-week interval between each visit. Platelet aggregation was evaluated by impedance aggregometry (Multiplate® Analyzer) using arachidonic acid (1.0 mM) and collagen (3.2 µg/ml) as agonists. Markers of platelet turnover were measured by flow cytometry. Compliance was confirmed by serum thromboxane B2. Platelet aggregation levels measured 1 and 24 hours after aspirin intake were compared using the mean of 1- and 24-hour measurements at the three study visits. The difference in platelet aggregation was 70 ± 97 AU × min (p < 0.0001) when using arachidonic acid as agonist and 33 ± 76 AU × min (p = 0.01) when using collagen. Markers of platelet turnover correlated positively, though not significantly, with residual platelet aggregation 24 hours after aspirin intake (p values 0.06 and 0.07). Median intra-individual variation of platelet aggregation was 9-16%. Patients with coronary artery disease and type 2 diabetes had increased platelet aggregation at the end of the 24-hour aspirin dosing interval. Platelet turnover did not correlate significantly with residual platelet aggregation, although a trend was observed. The intra-individual variation of platelet aggregation after aspirin intake was low.

Topics: Aged; Aspirin; Biomarkers; Blood Platelets; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane B2; Time Factors; Treatment Outcome

Aspirin is a cornerstone in management of coronary artery disease (CAD). However, considerable variability in the antiplatelet effect of aspirin has been reported.. To investigate independent determinants of reduced antiplatelet effect of aspirin in stable CAD patients.. We performed a cross-sectional study including 900 stable, high-risk CAD patients. Among these, 795 (88%) had prior myocardial infarction, 250 (28%) had type 2 diabetes, and 170 (19%) had both. All patients received 75 mg aspirin daily as mono antiplatelet therapy. The antiplatelet effect of aspirin was assessed by measurement of platelet aggregation employing 1) multiple electrode aggregometry (MEA, Multiplate Analyzer) in whole blood anticoagulated with citrate or hirudin using arachidonic acid (AA) or collagen as agonists, and 2) VerifyNow Aspirin Assay. Compliance was assessed by measurement of serum thromboxane B2.. Platelet count, prior myocardial infarction, type 2 diabetes and body mass index were independent determinants of increased AA-induced MEA platelet aggregation in citrate and hirudin anticoagulated blood (p-values ≤ 0.045). Similar results were found with VerifyNow. Prior coronary artery bypass grafting, age, smoking (MEA, AA/citrate) and female gender (MEA, AA/hirudin) were also independent determinants of increased platelet aggregation (p-values ≤ 0.038). Compliance was confirmed by low serum thromboxane B2 levels in all patients (median [25%;75%]: 0.97 [0.52;1.97], range 0.02-26.44 ng/ml).. Platelet count, prior myocardial infarction, type 2 diabetes and body mass index were independent determinants of increased platelet aggregation, indicating that these characteristics may be key factors in reduced antiplatelet effect of aspirin in stable CAD patients.

Topics: Aged; Aspirin; Body Mass Index; Coronary Artery Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Thromboxane B2

To elucidate the correlation between urinary 11-dehydro-thromboxane B2 (11dhTxB2) and clinical efficacy of aspirin treatment in patients with type 2 diabete and coronary artery disease (CAD).. In this prospective cohort study, 169 aged patients with type 2 diabete accompanying CAD in Peking University First Hospital were enrolled. The level of urinary 11dhTxB2 was detected using enzyme-linked immuno-sorbent assay. Low aspirin response or high on aspirin platelet reactivity (HAPR) was defined as urinary 11dhTxB2>1 500 ng/g. All the included patients were divided into two groups based on the results, HAPR group and No-HAPR group.. Baseline urinary 11dhTxB2 of the patients with type 2 diabete accompanying CAD was (3 687±3 052) ng/g, while the urinary 11dhTxB2 was (1 954±859) ng/g in patients after 100 mg/d aspirin treatment (P<0.001). Prevalence of HAPR in patients with type 2 diabete accompanying CAD were 32.5%. Within a mean follow-up time of 12 months, the outcomes occurred more frequently in HAPR group than in No-HAPR group (P<0.05).. Urinary 11dhTxB2 can be recognized as an effective indicator in evaluating aspirin clinical efficacy of patients with type 2 diabete accompanying CAD.

Topics: Aspirin; Beijing; Blood Platelets; Coronary Artery Disease; Diabetes Mellitus, Type 2; Humans; Platelet Aggregation Inhibitors; Prospective Studies; Thromboxane B2; Treatment Outcome

Dickkopf-1 (DKK-1) is a major regulator of the Wnt signaling pathway, involved in inflammation, atherogenesis, and the regulation of glucose metabolism. Because platelets are major contributors to circulating levels of DKK-1 in other clinical settings, we aimed at characterizing the platelet contribution to DKK-1 in type 2 diabetes mellitus (T2DM) and evaluating associations of DKK-1 with glucose metabolism, platelet activation, and endothelial dysfunction.. A cross-sectional comparison of DKK-1, soluble CD40L (sCD40L; reflecting platelet-mediated inflammation), asymmetric dimethylarginine (ADMA; marker of endothelial dysfunction), and urinary 11-dehydro-thromboxane B2 (in vivo marker of platelet activation) was performed among 214 diabetic patients (90 receiving aspirin at 100 mg/day) and 30 healthy controls. Plasma DKK-1 levels were markedly higher in patients with T2DM than in healthy patients (P<0.0001). DKK-1 levels were significantly lower in diabetic patients receiving compared with those not on aspirin treatment (P=0.008); in the latter, DKK-1 was significantly correlated with 11-dehydro-thromboxane B2, ADMA, and CD40L (ρ=0.303. P<0.0001, ρ=0.45. P<0.0001, and ρ=0.37, P<0.0001, respectively) but not with glycemic control or DM duration. Among patients not receiving aspirin, improvement of metabolic control in a subgroup of newly diagnosed patients treated with acarbose for 20 weeks and in a group treated with rosiglitazone for 24 weeks was associated with concurrent significant reductions in DKK-1 (P=0.005 and P=0.004) and 11-dehydro-thromboxane B2 (P=0.005 and P=0.004).. Circulating DKK-1 is increased in T2DM and associated with endothelial dysfunction and platelet activation. Plasma DKK-1 levels are reduced with improvement of glycemic control and low-dose aspirin treatment.

Topics: Aged; Arginine; Aspirin; Biomarkers; Cardiovascular Diseases; Case-Control Studies; CD40 Ligand; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Platelet Activation; Platelet Aggregation Inhibitors; Thromboxane B2; Wnt Signaling Pathway

The objective of this study was to investigate the association between plasma concentrations of salicylic acid (SA) and other minor acetylsalicylic acid (ASA) metabolites and high on ASA platelet reactivity assessed with different methods in type 2 diabetic patients (T2DM).. Study cohort consisted of 293 T2DM patients on chronic ASA therapy. Platelet function inhibition was analyzed using measurements of serum thromboxane B2 (S-TxB2), VerifyNow Aspirin and Platelet Function Analyzer (PFA)-100 assays. The concentration of ASA metabolites in plasma was measured with a high-performance liquid chromatography (HPLC).. In logistic regression analysis both ASA dose/kg of body weight and plasma SA concentration were found to be predictive of S-TxB2 concentrations above 0.72 ng/mL cut-off point (OR 16.9, 95% CI 2.29-125.8, p = 0.006 and OR 5.34, 95% CI 2.67-10.68, p < 0.001, respectively). When using the VerifyNow Aspirin Assay, the concentrations of SA were significantly lower (p = 0.007) in the group with high on ASA platelet reactivity when compared with the group with normal on ASA platelet reactivity. In logistic regression analysis plasma SA concentration was found to be predictive of VerifyNow Aspirin Reaction Units (ARU) ≥ 550 (OR 3.86, 95% CI 1.86-8.00, p < 0.001).. Our study suggests that disturbances of pharmacokinetic mechanisms might contribute to lower plasma SA levels, and subsequently incomplete inhibition of thromboxane A2 synthesis as measured with S-TxB2 concentrations and increased platelet reactivity measured with VerifyNow in T2DM patients.

Topics: Aged; Aspirin; Biomarkers; Blood Platelets; Chromatography, High Pressure Liquid; Coronary Artery Disease; Cyclooxygenase 1; Diabetes Mellitus, Type 2; Drug Resistance; Female; Humans; Logistic Models; Male; Middle Aged; Odds Ratio; Platelet Aggregation Inhibitors; Platelet Function Tests; Poland; Predictive Value of Tests; Prospective Studies; Risk Factors; Salicylic Acid; Thromboxane B2

Protective effects of two different extracts of TSCA (total saponins from Cicer arietinum) were studied on kidney of T2DM rats. The diabetic model group was established with high calorie feeding and small dose injection of streptozotocin (STZ, 45 mg x kg(-1)). DM rats were randomly assigned to model group (feed with propylene glycol 1 mL/100 g), TSCA high dose group (300 mg x kg(-1)), TSCA low dose group (100 mg x kg(-1)) and normal control group (feed with propylene glycol 1 mL/100 g). After four weeks treatment with TSCA I and II, the levels of FPG FIns, BUN, Scr, ATII, ET-1, TXB2 and 6-keto-PGF1alpha in blood and the activities of SOD, GSH-PX and MDA in kidney were analyzed by biochemical methods. After four weeks treatment with TSCA II, the levels of FPG FIns, BUN, Scr, ATII and ET-1 were reduced significantly; and the ratios of TXB2 to 6-keto-PGF1alpha and SOD were effectively alleviated in TSCA II group. While there is no significant change on FPG and BUN in comparison to the rats treated with TSCA I, Scr, ATII, ET-I, GSH-PX and SOD were alleviated. The results suggest that TSCA II could be used to reduce FPG and FIns. According to the result of vasoactive substances index, TSCA II is more effective than TSCA I on renal protection of DM rats.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Animals; Blood Glucose; Blood Urea Nitrogen; Cicer; Creatinine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endothelin-1; Glutathione Peroxidase; Hypoglycemic Agents; Insulin; Kidney; Male; Malondialdehyde; Plants, Medicinal; Random Allocation; Rats; Rats, Wistar; Saponins; Superoxide Dismutase; Thromboxane B2

Previous studies have demonstrated considerable variation in the antiplatelet effect of aspirin.. To investigate the impact of platelet turnover on the antiplatelet effect of aspirin in patients with stable coronary artery disease (CAD) and to identify determinants of platelet turnover.. Platelet turnover was evaluated by measurements of immature platelets and thrombopoietin in 177 stable CAD patients on aspirin monotherapy, including 85 type 2 diabetics and 92 non-diabetics. Whole blood platelet aggregation was determined using the VerifyNow(®) Aspirin test and multiple electrode aggregometry (MEA, Multiplate(®) ) induced by arachidonic acid (AA) (1.0 mm), adenosine diphosphate (ADP) (10 μm) and collagen (1.0 μg mL(-1) ).. Immature platelet levels significantly correlated with MEA (r = 0.31-0.36, P-values < 0.0001) and the platelet activation marker sP-selectin (r = 0.19, P = 0.014). Contrary to the VerifyNow(®) test, MEA significantly correlated with variations in platelet count (r = 0.45-0.68, P-values < 0.0001). Among patients with residual platelet reactivity according to AA, there were significantly more diabetics (61% vs. 41%, P = 0.027) and higher levels of sP-selectin (77.7 ± 29 vs. 70.2 ± 25 ng mL(-1) , P = 0.070) and serum thromboxane B(2) (0.81 [0.46; 1.70] vs. 0.56 [0.31; 1.12] ng mL(-1) , P = 0.034). In a multivariate regression analysis, immature platelet levels were determined by thrombopoietin levels (P < 0.001), smoking (P = 0.020) and type 2 diabetes (P = 0.042).. The antiplatelet effect of aspirin was reduced in CAD patients with an increased platelet turnover. Once-daily dosing of aspirin might not suffice to adequately inhibit platelet aggregation in patients with an increased platelet turnover.

Topics: Adenosine Diphosphate; Aged; Arachidonic Acid; Aspirin; Biomarkers; Blood Platelets; Case-Control Studies; Chi-Square Distribution; Collagen; Coronary Artery Disease; Denmark; Diabetes Mellitus, Type 2; Female; Humans; Linear Models; Male; Middle Aged; P-Selectin; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Platelet Function Tests; Registries; Risk Assessment; Risk Factors; Smoking; Thrombopoietin; Thromboxane B2

Diabetic patients commonly present an increased risk for cardiovascular events, for which aspirin is the most frequently used medication for primary prevention. Urinary 11-dehydro thromboxane (11-dhTXB₂) concentrations assess the effect of aspirin on platelets and identify patients who are at risk of cardiovascular events. The present study investigated whether or not type 2 diabetic patients who took a daily dose of 100mg of aspirin had a significant reduction in urinary 11-dhTXB₂ concentrations and whether these results were associated with clinical and laboratory variables.. Eighty-one type 2 diabetic patients were enrolled in the study. Laboratory tests included the determination of lipidic profile, glycated hemoglobin, platelets count, molecular analysis for both GPIIbIIIa and COX-1 polymorphisms, and urinary 11-dhTXB₂.. Patients' median value for urinary 11-dhTXB₂ before aspirin intake was 179 pg/mg of creatinine. After 15days taking aspirin, the patients presented median of 51 pg/mg of creatinine, thus revealing a significant difference between medians (p=0.00). A reduction of 95% in urinary 11-dhTXB₂ concentrations could only be identified in 4 patients (5%). A BMI of ≥ 26 presented a significant association with a reduction of urinary 11-dhTXB₂ concentrations (p=0.010), as shown by the multiple logistic regression model. Other clinical and laboratory variables showed no association.. Regardless of the mechanisms related to aspirin non-responsiveness, most patients enrolled in the present study also presented a reduced or minimal response to low-dose aspirin therapy, thereby indicating a clear variability related to aspirin effectiveness. Moreover, BMI appears to be independently associated to the reduction of urinary 11-dhTXB₂ concentrations in type 2 diabetic patients taking aspirin.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Diabetes Mellitus, Type 2; Humans; Male; Middle Aged; Thromboxane B2

Platelet hyperactivation contributes to the increased risk for atherothrombosis in type 2 diabetes and is associated with oxidative stress. Plasma low-density lipoproteins (LDLs) are exposed to both hyperglycemia and oxidative stress, and their role in platelet activation remains to be ascertained.. The aim of this study was to investigate the effects of LDLs modified by both glycation and oxidation in vitro or in vivo on platelet arachidonic acid signaling cascade. The activation of platelet p38 MAPK, the stress kinase responsible for the activation of cytosolic phospholipase A(2), and the concentration of thromboxane B(2), the stable catabolite of the proaggregatory arachidonic acid metabolite thromboxane A(2), were assessed.. First, in vitro-glycoxidized LDLs increased the phosphorylation of platelet p38 MAPK as well as the concentration of thromboxane B(2). Second, LDLs isolated from plasma of poorly controlled type 2 diabetic patients stimulated both platelet p38 MAPK phosphorylation and thromboxane B(2) production and possessed high levels of malondialdehyde but normal alpha-tocopherol concentrations. By contrast, LDLs from sex- and age-matched healthy volunteers had no activating effects on platelets.. Our results indicate that LDLs modified by glycoxidation may play an important contributing role in platelet hyperactivation observed in type 2 diabetes via activation of p38 MAPK.

Topics: Blood Glucose; Blood Platelets; Diabetes Mellitus, Type 2; Female; Glycoproteins; Humans; In Vitro Techniques; Lipoproteins, LDL; Male; Malondialdehyde; Middle Aged; Oxidation-Reduction; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Platelet Activation; Thromboxane B2

To investigate the relationship between syndrome differentiation of traditional Chinese medicine (TCM) and characteristic changes of vascular endothelial function in patients with diabetic arterial occlusion (DAO) of lower extremities.. Forty patients with DAO were selected as trial group. Twenty patients among them were attributed to blood stasis syndrome (group A1), and the others were attributed to syndrome of pathogenic dampness-heat attacking the lower limb (group A2) according to syndrome differentiation type of TCM. Patients with diabetes (group B), arteriosclerosis obliterans (group C) and healthy people (group D) were observed as the control groups, respectively. There were 20 cases in each group. Endothelium-dependent dilation (EDD) and endothelium-independent dilation (EID) were measured by high resolution ultrasound in the 100 subjects and the changes of vascular tension factors were also studied.. The results showed that EDD in group A was reduced significantly as compared with that in the groups B, C and D. The levels of vascular contractile factors such as endothelin-1 (ET-1) and thromboxane B2 (TXB2) in group A were higher than those in the groups B, C and D, while the levels of vascular dilatory factors such as nitric oxide (NO) and 6-keto-prostaglandin F1alpha(6-Keto-PGF1alpha) were declined significantly as compared with those in the groups B and D. Linear correlation analysis showed that EDD was correlated positively with the levels of NO and 6-Keto-PGF1alpha, while the levels of ET-1 and TXB2 had negative correlation with EDD. EDD and EID in group A2 were declined significantly as compared with those in group A1.. Our findings indicate that endothelial dysfunction may play an important role in the pathogenesis of DAO and may be associated with syndrome differentiation of TCM.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Arterial Occlusive Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diagnosis, Differential; Endothelin-1; Endothelium, Vascular; Female; Humans; Lower Extremity; Male; Medicine, Chinese Traditional; Middle Aged; Nitric Oxide; Thromboxane B2

We evaluated the vascular reactivity in healthy subjects, heavy smokers, uncompensated type II diabetics, and patients with uncontrolled essential hypertension. Plasma nitrite/nitrate, cyclic 3',5'-guanosine monophosphate (cGMP), and thromboxane (TX)-B(2) levels were measured.. One hundred participants were classified into four groups: normal control subjects (n = 25), heavy smokers (n = 25), uncompensated type II diabetics (n = 25), and patients with uncontrolled essential hypertension (n = 25).. The brachial artery diameter was measured by a high-resolution ultrasound technique before and after reactive hyperemia and glyceryl trinitrate (GTN), 0.4 mg, administration. Plasma nitrite/nitrate, cGMP, and TX-B(2) levels were also measured.. Heavy smokers, uncompensated type II diabetics, and uncontrolled hypertensive patients showed impaired endothelium-dependent, nitric oxide (NO) flow-mediated vasodilatation (8.0 +/- 2.5%, 5.8 +/- 2.7%, and 7.2 +/- 3.3%, respectively [mean +/- SD]) when compared to the control subjects (12.6 +/- 3.6%; p < 0.01). Smokers had a normal endothelium-independent function induced by NO donor (GTN) [25.0 +/- 7.3% vs 25.3 +/- 8.5% for control subjects]. Uncompensated type II diabetics and patients with uncontrolled hypertension had impaired endothelium-independent responses (17.7 +/- 7.1% and 16.8 +/- 6.9%, respectively, vs 25.3 +/- 8.5 for normal control subjects; p < 0.05). Plasma levels of cGMP and TX-B(2) were not significantly different in the four groups, but nitrite/nitrate concentrations were increased in diabetics compared to the control subjects (266 +/- 47 micro mol/L vs 98 +/- 18 micro mol/L, p < 0.05).. Both uncontrolled hypertension and type II diabetes mellitus, but not smoking, are associated with impaired vascular smooth-muscle reactivity induced by NO donors. However, only uncompensated type II diabetics showed an increase in plasma nitrite/nitrate levels, suggesting an association with excessive production and/or inactivation of NO.

Topics: Adult; Blood Flow Velocity; Cyclic GMP; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Hyperemia; Hypertension; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Nitroglycerin; Smoking; Thromboxane B2; Vasodilation; Vasodilator Agents

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

To determine cytochrome P450 (CYP450) and cyclooxygenase (COX) expression and metabolite regulation and renal damage in the early stages of obesity-related hypertension and diabetes.. Obese and lean Zucker rats at 10 to 12 weeks of age were studied. Blood pressure was measured in the conscious state using radiotelemetry. Blood glucose levels and body weight were measured periodically. Protein expression of CYP450 and COX enzymes in the kidney cortex, renal microvessels, and glomeruli was studied. The levels of CYP450 and COX metabolites in urine were measured, and urinary albumin excretion, an indicator of kidney damage, was measured.. Body weight and blood glucose averaged 432 +/- 20 grams and 105 +/- 5 mg/dl, respectively, in obese Zucker rats as compared with 320 +/- 8 grams and 91 +/- 5 mg/dl, respectively, in age-matched 10- to 12-week-old lean Zucker rats. Renal microvascular CYP4A and COX-2 protein levels were increased 2.3- and 17.0-fold, respectively, in obese Zucker rats. The protein expression of CYP2C11 and CYP2C23 was decreased 2.0-fold in renal microvessels isolated from obese Zucker rats when compared with lean Zucker rats. The urinary excretion rate of thromboxane B(2) was increased significantly in obese Zucker as compared with lean Zucker rats (22.0 +/- 1.8 vs. 13.4 +/- 1.0 ng/d). Urinary albumin excretion, an index of kidney damage, was increased in the obese Zucker rat at this early age.. These results suggest that increased CYP4A and COX-2 protein levels and decreased CYP2C11 and CYP2C23 protein levels occur in association with microalbuminuria during the onset of obesity-related hypertension and type 2 diabetes.

Topics: Albuminuria; Animals; Aryl Hydrocarbon Hydroxylases; Blood Glucose; Body Weight; Cyclooxygenase 2; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 2; Diabetes Mellitus, Type 2; Hypertension; Isoenzymes; Kidney; Kidney Cortex; Kidney Glomerulus; Male; Microcirculation; Obesity; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Zucker; Steroid 16-alpha-Hydroxylase; Thromboxane B2

To study the change of vascular tension factors (VTF), including vascular contractile factors as endothelin-1 (ET-1), thromboxane A2 (TXA2) and vascular dilatory factors as nitric oxide (NO), prostacyclin (PGI2), in different stage of peripheral diabetic arterial occlusion (PDAO), and to preliminarily explore the clinical significance of these changes.. VTF in 40 diabetic patients, 15 of 2nd stage and 25 of 3rd stage, were observed by measuring level of ET-1, NO, TXB2 and 6-keto-PGF1alpha in blood plasma with RIA assay.. (1) ET-1 and TXB2 levels in all patients were higher than those in control (P < 0.05 and P < 0.01), those in patients of 3rd stage was higher than those of 2nd stage, showing significant difference (P < 0.05). (2) NO and 6-keto-PGF1alpha levels in all patients was lower than those in control, but showed no significant difference between patients of various stages (P > 0.05).. There are changes of VTF in patients with PDAO, manifesting as increase of vascular contractive factors and decrease of vascular dilative factor. The changes are diffrent in various stages, the vascular contractive and thrombotic factors in patients of 3rd stage are higher than those in patients of 2nd stage, but the injury on vascular dilative factors in the two stages showed insignificant difference.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelin-1; Epoprostenol; Female; Humans; Lower Extremity; Male; Middle Aged; Nitric Oxide; Thromboxane A2; Thromboxane B2; Vasomotor System

Diabetes mellitus (DM) is associated with enhanced lipid oxidation and persistent platelet activation. We investigated whether oxidant stress (OS) also affects circulating proteins and is associated with an abnormal coagulative pattern. In 72 type 2 DM (T2DM) patients, urinary 8-iso-prostaglandin (PG) F2alpha and 11-dehydro-thromboxane B2 (TXM) were measured as markers of lipid peroxidation and platelet activation, respectively. The carbonyl content of plasma proteins (PCARB) was measured as global index of protein oxidation. 8-Iso-PGF2alpha and PCARB levels were higher in DM patients than in controls (P < 0.05). Likewise, both TXM and prothrombin F1+2 levels were higher in diabetics (P < 0.05). By contrast, anticoagulant markers, such as activated protein C, protein C activation peptide, and soluble thrombomodulin (TM) were depressed in T2DM (P < 0.05). In conclusion, OS in T2DM involves circulating proteins and is associated with an unbalanced promotion of procoagulant reactions. These effects in concert with platelet activation may contribute to atherothrombotic complications in T2DM.

Topics: Aged; Aged, 80 and over; Biomarkers; Blood Proteins; Case-Control Studies; Diabetes Mellitus, Type 2; Dinoprost; F2-Isoprostanes; Female; Hemostasis; Humans; Lipid Peroxidation; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Platelet Activation; Thrombosis; Thromboxane B2

To investigate associations between structural, functional and circulatory placental changes in pregnancies complicated by impaired glucose metabolism.. Umbilical artery (UA) blood flow resistance was measured by Doppler velocimetry in 21 gravidae with diabetes/impaired glucose tolerance (IGT) and 10 healthy gravidae. Umbilical and placental vessel segments were incubated for determination of prostacyclin and thromboxane synthesis, and tissues histologically examined. Non-parametric statistical tests at a two-tailed P<0.05 were used.. Placental lesions were more common in diabetes/IGT and, although not being an uniform finding, in general associated with a higher vascular synthesis of thromboxane and/or lower prostacyclin/thromboxane synthesis ratio. As an exception, ischemic villitis was associated with a higher ratio and higher UA flow resistance.. Placental lesions are associated with an altered vascular prostanoid synthesis in diabetes/IGT, but not until structural signs of ischemia develop is a rise of UA blood flow resistance detected.

Topics: 6-Ketoprostaglandin F1 alpha; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Glucose Intolerance; Humans; Infarction; Ischemia; Placenta; Placenta Diseases; Pregnancy; Pregnancy in Diabetics; Thrombosis; Thromboxane B2; Umbilical Arteries; Vascular Resistance

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Diabetes Mellitus, Type 2; Epoprostenol; Female; Humans; Male; Reproducibility of Results; Research Design; Thromboxane B2

Enhanced platelet function, particularly in response to collagen, is a common occurrence in diabetes that increases the risk of cardiovascular disease. Ginkgo biloba extract is ingested primarily to improve mental focus but it possesses a blood-thinning potential, which has not been well characterized. This study was designed to compare the effect of ingesting G. biloba extract on platelet aggregation in platelet-rich plasma (PRP) and prostanoid urinary excretion in healthy volunteers and subjects with Type 2 diabetes mellitus (T2DM). Before and after ingesting 120 mg of standardized G. biloba extract for 3 months, platelet aggregation was studied in PRP and urinary metabolites of thromboxane B(2) (TXB(2)) and prostacyclin (PGI(2)) were measured. In healthy volunteers (age, 42+/-11 years; BMI, 28.4+/-4.8 kg/m(2); n=28), the ingestion of G. biloba extract significantly increased fasting insulin and C-peptide (10+/-4 vs. 12+/-6 microU/ml, p<0.007 and 1.3+/-0.8 vs. 2.1+/-1.1 ng/ml, p<0.001, respectively) and significantly reduced collagen but not PAF-mediated platelet aggregation, converting 21 of 28 subjects with [COL+/EPI+] platelets to the [COL-/EPI+] phenotype. This was accompanied by a reduction of 11-dehydro-TXB(2) from 12.4+/-6.1 to 10.3+/-6.1 ng/mg Cr (p<0.04) and PGI(2) metabolites (2,3-dinor-6-keto-PGF(1alpha) and 6-keto-PGF(1alpha)) from 2.2+/-0.8 to 1.8+/-0.8 ng/mg Cr (p<0.05). In the T2DM subjects (age, 54+/-8; BMI, 36.6+/-7.9 kg/m(2); n=19), G. biloba ingestion did not affect pancreatic beta-cell function but significantly reduced platelet aggregation, converting 16 of 19 [COL+/EPI+] platelets to the [COL-/EPI+] phenotype. Unlike the healthy volunteers, this was not accompanied by a reduced urinary prostanoid excretion. G. biloba-induced reduction of both classes of prostanoid metabolites in healthy volunteers, but not in T2DM subjects, may suggest a nonselective inhibition of COX-1-mediated TXA(2) in platelets and COX-2-mediated PGI(2) production by the endothelial cells and perhaps platelet-enriched levels of arachidonic acid or COX-1 activity, or both, in T2DM subjects.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Case-Control Studies; Diabetes Mellitus, Type 2; Drug Interactions; Female; Ginkgo biloba; Humans; Male; Middle Aged; Phytotherapy; Plant Extracts; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandins; Thromboxane B2

Cerebrovascular disease and other vascular diseases are common complications of non-insulin-dependent diabetes mellitus (NIDDM) and are associated with its increased morbidity and mortality. Platelet activation plays an important role in the pathomechanisms of these vascular diseases. Although several indices have been used to assess platelet activation, few data are available indicating which are more sensitive or more valuable in this situation. We have measured platelet arachidonic acid metabolites [thromboxane B2 (TXB2) and 11-dehydro-thromboxane B2 (TXB2)] and plasma P-selectin, platelet fibrinogen binding and membrane glycoproteins in 47 well-characterized NIDDM patients with cerebrovascular disease, 38 NIDDM patients without vascular diseases, and 36 age-matched healthy individuals. Our study shows that platelets were remarkably activated in NIDDM patients with cerebrovascular diseases. The measurement of plasma 11-dehydro-TXB2 and the determination of fibrinogen binding to, and P-selectin expression on platelets would reveal a higher diagnostic sensitivity for detecting in vivo platelet activation than other markers.

Topics: Adult; Aged; Arachidonic Acid; Biomarkers; Blood Platelets; Cerebrovascular Disorders; Diabetes Mellitus, Type 2; Humans; Middle Aged; P-Selectin; Platelet Activation; Platelet Glycoprotein GPIb-IX Complex; Platelet Glycoprotein GPIIb-IIIa Complex; Thromboxane B2

To elucidate the relationship between the thromboxane A2/prostacyclin (TXA2/PGI2) ratio and diabetic complications, the levels of 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1alpha, the urinary metabolites of thromboxane A2 and prostacyclin, were measured in diabetics by gas chromatography/selected ion monitoring. We compared the TXA2/PGI2 ratio in healthy volunteers and diabetics. The TXA2/PGI2 ratio of diabetics was significantly higher than that of healthy volunteers and we could reconfirm the hypercoagulable condition in diabetics. We also investigated the difference of TXA2/PGI2 levels in diabetics with retinopathy and neuropathy. The TXA2/PGI2 ratio of diabetics with retinopathy showed significantly higher level than without retinopathy. However, the TXA2/PGI2 ratio of diabetics with neuropathy was the same as without neuropathy. These results suggest that the TXA2/PGI2 ratio reflects the pathological conditions of diabetes, especially the change of vasculature. The monitoring and improvement of TXA2/PGI2 ratio could be useful for the prevention of diabetic vascular complications.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Chromatography, Gas; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Epoprostenol; Female; Humans; Male; Thromboxane B2

In an investigation of the involvement of prostanoids in the pathogenesis of nephropathy in type 2 diabetes, we repeatedly measured the urinary excretion of prostanoids in both diabetic and healthy rats as the rats aged. Seven rats of the Otsuka Long-Evans Tokushima Fatty strain were used as rats with a model of type 2 diabetes and seven rats of the Long-Evans Tokushima Otsuka strain were used as rats without diabetes. Thromboxane (TX) B2 and 6-keto-prostaglandin (PG) F1alpha, the amounts of which reflect renal production of TXA2 and PGI2, respectively, and PGE2 in urine collected in metabolic cages were assayed when rats were 14, 30, 46, and 54 weeks old. Plasma glucose and urinary protein excretion also were measured periodically. The mean plasma glucose concentration of the diabetic rats was higher than that of the healthy rats throughout the study. At 30 weeks and later, urinary protein excretion by the diabetic rats was greater than that of the healthy rats, and it increased with age. Urinary excretion of TXB2 by the diabetic rats was higher than that of the healthy rats at 14 weeks (52.4+/-23.5 vs. 27.0+/-2.6 ng/day; mean +/- SD, P = .015) and the difference continued to the end of the experiment. Urinary excretion of 6-keto-PGF1alpha by the diabetic rats was high at 14 weeks (52.3+/-12.8 vs. 26.9+/-4.6 ng/day; mean +/- SD, P<.001) but decreased with age and was the same as that of the healthy rats at 54 weeks. The urinary excretion of PGE2 by the two groups of rats was not significantly different. These results suggest that altered renal production of TXA2 and PGI2 is involved in the pathogenesis of diabetic nephropathy in rats with type 2 diabetes.

Topics: 6-Ketoprostaglandin F1 alpha; Aging; Animals; Blood Glucose; Body Weight; Creatinine; Diabetes Mellitus, Type 2; Dinoprostone; Disease Models, Animal; Kidney; Male; Prostaglandins; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Thromboxane B2; Thromboxanes

Having developed a non-insulin-dependent diabetes mellitus (NIDDM) syndrome model in the rabbit using Wirsung duct ligation, it appeared interesting to use it to study the relationship between glycemia and the plasma levels of TXA(2)and PGI(2), and of some other biochemical parameters such as cholesterol, triglycerides, alkaline phosphatase and transaminases. A comparative study was carried out in the sham-operated rabbits (controls, C) and those having their pancreatic duct ligatured (NIDDM, D) at 15, 30, 40, 50 and 60 days post-ligation. On the 40th days, whereas in the controls, glycemia was 1.17 +/- 0.04 g.l(-1), it reached a maximum of 4.62 +/- 0.76 g.l(-1)(25.40 mM) in the NIDDMs. No significant modification was observed either in cholesterolemia or in triglyceridemia in either group. The GOT and GPT were highly increased, from 11.50 +/- 4.00 IU. l(-1)and 27.00 +/- 1.50 IU.l(-1)(C) to 37.50 +/- 5.64 IU.l(-1)(P<0. 001) and 58.50 +/- 7.50 IU.l(-1)(D) (P<0.001) in the NIDDM group, suggesting that hyperglycemia occurred simultaneously with the degeneration of the pancreatic tissue. In parallel, in D rabbits, the plasma levels of TXB(2)and 6 keto PGF(1alpha)were augmented to 68.22 +/- 6.20 pg.ml(-1)versus 22.49 +/- 5.74 pg.ml(-1)(C) (P<0.001), and 127.11 +/- 14.39 pg.ml(-1)versus 48.65 +/- 4.51 pg.ml(-1)(C) (P<0. 001) respectively. Statistical studies showed a significant correlation (P<0.05 and <0.02) between glycemia and the biosynthesis of eicosanoids under study. Moreover, 25 mM was found to be the threshold level of glucose excess essential to increase the TXA(2)and PGI(2)biosynthesis significantly. This supports the results obtained by other authors studying the action of glucose on phospholipase activity and consequent eicosanoid production.

Topics: 6-Ketoprostaglandin F1 alpha; Alkaline Phosphatase; Animals; Blood Glucose; Blood Proteins; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Epoprostenol; Hyperglycemia; Ligation; Pancreatic Ducts; Platelet Aggregation Inhibitors; Rabbits; Thromboxane A2; Thromboxane B2; Time Factors; Transaminases

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

We have previously shown that low-density (LDL) and high-density (HDL) lipoprotein from healthy subjects can promote in vitro prostaglandin (PG) release by murine macrophages. In this pilot study, we have measured PG production induced by lipoproteins of six diabetic patients with poor metabolic control, compared to five healthy controls. Plasma lipoprotein levels were similar in both groups. Lipoprotein fractions were purified by sequential ultracentrifugation. After lipoprotein incubation with cells, supernatants were extracted and PG quantified by HPLC. In presence of LDL, in control subjects, there was an increase in total PG production, mainly due to thromboxane B2 (TxB2). In diabetic patients, the secretion pattern was similar. In presence of HDL, in control subjects, total PG secretion was also increased, but it was balanced between TxB2 and prostacyclin. In diabetic patients, at low HDL concentration (10 mg/l) the secretion was mainly due to TxB2, while at higher HDL concentrations (100 mg/l). the secretion was balanced between TxB2 and prostacyclin. Comparison of means of areas under curve for the two groups studied showed that LDL increased all PG secretion in diabetic patients compared to controls (P < 0.05 for PGF2alpha), while HDL increased all PG secretion in controls compared to diabetic patients, except PGF2alpha. Our work suggests a key role of LDL in TxB2 secretion in diabetic patients, which is a major proaggregant and vasoconstrictive agent. There was also an increased secretion of all PG in diabetic patients.

Topics: Animals; Diabetes Mellitus, Type 2; Epoprostenol; Female; Humans; Leukemia P388; Lipoproteins, HDL; Lipoproteins, LDL; Macrophages; Male; Mice; Prostaglandins; Thromboxane B2; Tumor Cells, Cultured

Thromboxane B2, a stable metabolite of thromboxane A2, was studied in type 2 diabetic patients to evaluate the role played by prostaglandins in the onset of vascular complications.. The study was carried out in 30 subjects, 20 of whom were diabetics and 10 controls. Thromboxane B2 was assayed using the "Biotrak Thromboxane B2" kit.. In the first group of control subjects, the mean value of TXB2 was 6.39 +/- 0.89 pg/ml; in the second group, including diabetic patients without vascular complications, TXB2 levels were 8.89 +/- 1.51; in the third, consisting of diabetic patients with microangiopathy, the mean level was 46.28 +/- 6.82; in the fourth, including patients with micro- and macroangiopathy, the mean level was 98.78 +/- 17.15; the fifth group, with a mean value of 41.00 +/- 9.86, included diabetic patients with cerebral vasculopathy. Thromboxane B2 was correlated with glycemia but the results were not statistically significant (r = 0.28; p < 0.05). The correlation with the years since onset of diabetes was positive and statistically significant (r = 0.49; p < 0.05).. In conclusion, the authors emphasise that TXB2 is present in the circulation in diabetes in steadily increasing quantities over time since the onset of diabetes, leading to chronic vasoconstriction which in turn leads to a deterioration of vascular lesions in the districts where hypoglycemia has already caused the activation of neurotransmitter hormones with consequent slowing down of the blood flow and progressive tissue hypoxia.

Topics: Age of Onset; Blood Glucose; Cerebrovascular Disorders; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Middle Aged; Prostaglandins; Thromboxane A2; Thromboxane B2; Vasoconstriction

Severe reproductive dysfunction has been described in non-insulin-dependent diabetes mellitus (NIDDM), correlated with high glucose levels in the plasma. We have characterized an abnormal prostanoid profile in tissues from NIDDM rats, and a tight correlation between nitric oxide (NO) levels and prostaglandin production. Likewise, we have determined that parturition is delayed in NIDDM rats compared to control animals. In order to characterize the events which precede delayed parturition in NIDDM rats, we evaluate (a) the arachidonic acid (AA) conversion in placental tissue obtained from control (day 21 and 22) and NIDDM (day 21, 22 and 23) late pregnant rats into prostaglandin E2 (PGE2) and F2alpha (PGF2alpha), thromboxane B2 (TXB2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), and (b) NO synthase (NOS) activity in control and NIDDM late pregnant animals. Placental arachidonate conversion from control rats into different prostanoids, namely PGE2, PGF2alpha, and TXB2, is higher in day 22 than in day 21, and radioconversion from diabetic rats into PGE2, PGF22, TXB2 and 6-keto-PGF1alpha on day 23 is higher than in day 21 and 22. 6-keto-PGF1alpha is lower and TXB2 is higher in diabetic tissues than in control. Placental AA conversion of control diabetic tissues on the day of delivery is decreased by N(G) monomethyl-L-arginine (LNMMA) (600 mM), a well known NOS inhibitor, while prostanoid production remains unaltered on previous days. NOS activity is higher in control on day 22 when compared to day 21, and in diabetic on day 23 when compared to day 22 of pregnancy. We conclude that elevated NO placental levels are observed in control (day 22) and NIDDM (day 23) rats, and may increase placental prostaglandin production on the day of delivery.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Diabetes Mellitus, Type 2; Dinoprost; Dinoprostone; Enzyme Inhibitors; Female; Gestational Age; Male; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Placenta; Pregnancy; Pregnancy in Diabetics; Prostaglandins; Rats; Rats, Wistar; Reference Values; Thromboxane B2

Severe uterine and placental disturbances have been described in diabetes pathology. The relative severity of these changes appears to correlate with high glucose levels in the plasma and incubating environment. In order to characterize changes in eicosanoid production we compared uterine and placental arachidonic acid conversion from control and non-insulin-dependent diabetes mellitus (NIDDM) rats on day 21 of pregnancy, into different prostanoids, namely PGE2, PGF22alpha, TXB2 (indicating the production of TXA2) and 6-keto-PGF1 (indicating the generation of PGI2). PGE2, PGF2alpha and TXB2 production was higher and 6-keto-PGF1alpha was similar in diabetic compared to control uteri. PLA2 activity was found diminished in the NIDDM uteri in comparison to control. A role for PLA2 diminution as a protective mechanism to avoid prostaglandin overproduction in uterine tissue from NIDDM rats is discussed. Placental tissues showed an increment in TXB2 generation and a decrease in 6-keto PGF1alpha level in diabetic rats when compared to control animals. Moreover, when control uterine tissue was incubated in the presence of elevated glucose concentrations (22 mM), similar generation of 6-keto PGF1alpha and elevated production of PGE2, PGF2alpha and TXB2 were found when compared to those incubated with glucose 11 mM. Placental TXB2 production was higher and 6-keto PGF1alpha was lower when control tissues were incubated in the presence of high glucose concentrations. However, high glucose was unable to modify uterine or placental prostanoid production in diabetic rats. We conclude that elevated glucose levels induced an abnormal prostanoid profile in control uteri and placenta, similar to those observed in non-insulin-dependent diabetic tissues.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dinoprost; Dinoprostone; Eicosanoids; Female; Maternal-Fetal Exchange; Placenta; Pregnancy; Pregnancy in Diabetics; Pregnancy, Animal; Prostaglandins A; Rats; Rats, Wistar; Thromboxane A2; Thromboxane B2; Uterus

1. The obese fa/fa Zucker rat is a genetic model of obesity and insulin resistance which develops a number of metabolic and endocrine features of non-insulin-dependent diabetes, including hypertension, proteinuria and glomerular sclerosis. 2. We have investigated the urinary excretion of the metabolites of thromboxane (thromboxane B2) and prostacyclin (6-keto prostaglandin F1 alpha), and of endothelin and cyclic GMP as markers for changes in the balance of renal haemodynamic factors in the obese Zucker rat. 3. Obese fa/fa Zucker rats were hypertensive compared with their lean counterparts (161 +/- 3 and 138 +/- 3 mmHg respectively, P < 0.01); obese animals were also markedly proteinuric (16.7 +/- 6.7 versus 1.1 +/- 0.1 mg/ml) and albuminuric (8.3 +/- 2.9 versus 0.4 +/- 0.25 mg/ml) and excreted less creatinine than lean animals (all P < 0.01). Urinary excretion of endothelin was greater in obese rats (123 +/- 24 versus 62 +/- 10 pg/15 h, P < 0.05) as was the level of pre-proendothelin mRNA, but excretion of cyclic GMP was depressed (12.5 +/- 1.6 versus 27.2 +/- 3.1 nmol/ 15 h, P < 0.01). Histological examination of kidneys from obese animals showed evidence of focal glomerulosclerosis and cortical tubular damage. 4. These results show that increased urinary endothelin is associated with proteinuria and early stage nephropathy in this animal model of non-insulin-dependent diabetes mellitus. This finding, coupled with a decreased excretion of cyclic GMP, suggests that these increased renal vasoconstrictor/vasodilator forces might contribute to the renal functional changes in non-insulin-dependent diabetes mellitus.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Animals; Cyclic GMP; Diabetes Mellitus; Diabetes Mellitus, Type 2; Endothelin-1; Immunohistochemistry; Kidney; Male; Obesity; Rats; Rats, Zucker; RNA, Messenger; Statistics, Nonparametric; Thromboxane B2

Activity of erythrocyte superoxide dismutase (RBC-SOD), levels of serum malondialdehyde (MDA), plasma 6-keto-prostaglandin F 1 alpha (6-keto-PGF 1 alpha) and thromboxane B2(TXB2) were measured in 30 healthy subjects and 57 coronary heart desease (CHD) patients inoluding 21 cases complicated with diabetes and 36 without. Their characteristics of Syndrome Differentiation and typing were observed. The results showed that the activity of RBC-SOD, 6-keto-PGF 1 alpha in CHD patients were significantly lower than those in the healthy subjects, but the levels of TXB2, MDA were significantly higher. The levels of TXB2 in CHD patients with diabetes were significantly higher than tose without, but the activity of RBC-SOD were significantly lower. There were remarkably positive correlations between the levels of serum MDA and that of blood sugar, TXB2, TG and BMI in CHD patients with diabetes. There were remarkably negative correlations between the levels of serum MDA and plasma 6-keto-PGF 1 alpha. The results suggested that the metabolic abnormality of lipoperoxides was more serious in CHD patients with diabetes than without. The main Syndrome of CHD with diabetes was Qi-Yin Deficiency with Blood Stasis, while that of without diabetes was Qi Deficiency with Blood Stasis.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Pressure; Coronary Disease; Diabetes Mellitus, Type 2; Diagnosis, Differential; Female; Humans; Lipid Peroxides; Male; Medicine, Chinese Traditional; Middle Aged; Superoxide Dismutase; Thromboxane B2; Yin Deficiency

We microanalyzed 2,3-dinor-6-keto-prostaglandin F1 alpha (2,3-dinor-6-keto-PGF1 alpha 1) and 11-dehydrothromboxane B2 (11-dehydro-TXB2, 2) in human urine. Samples containing a [2H4]-analogue as an internal standard were extracted by chromatography using Sep Pak tC18 and silica gel. The compounds were then analysed by means of the lactone ring opening reaction and dimethylisopropylsilylation. The conversion of 1 to 1-methyl ester (ME)-propylamide (PA)-9, 12, 15-dimethylisopropylsilyl (DMIPS) ether derivative and of 2 to 1-ME-6-methoxime (MO)-9, 12, 15-tris-DMIPS ether derivative was followed by gas chromatography/selected ion monitoring (GC/SIM). Interfering substances from the urine matrix were eliminated during GC/SIM analysis using a DB-5 column. We were able to detect 1 (222-1031 pg/mg creatinine) and 2 (18-155 pg/mg creatinine) in human urine. Furthermore, the thromboxane/prostacyclin (IX/PGI) ratio in the urine of diabetics was higher than that of healthy volunteers. This method can be used to determine the TX/PGI balance in human urine.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Chromatography, Gas; Deuterium; Diabetes Mellitus, Type 2; Epoprostenol; Female; Humans; Male; Reference Values; Thromboxane B2

In this study, we investigated the effect of captopril (CPT) on glomerular filtration rate (GFR), effective renal plasma flow (ERPF), filtration fraction (FF), urinary albumin excretion (UAE) and daily urinary excretion of thromboxane B2 (TXB2) and 6-keto- prostaglandin F1a (6-keto-PGF1a) in 29 normotensive non-insulin-dependent diabetes (NIDDM) patients without clinically discernible nephropathy. Before treatment, urinary excretion 6-keto-PGF1a was significantly increased (P < 0.05) in 29 NIDDM patients compared with 25 health subjects matched for age and sex. The values of GFR and FF were significantly higher (P < 0.01 and P < 0.005, respectively) in NIDDM than in normal volunters, whereas ERPF was comparable in both groups. Meanwhile we observed that UAE of early NIDDM was increased before treatment. After CPT treatment, GFR, FF, UAE and urinary excretion of 6-keto-PGF1a were significantly reduce (all P < 0.005) compared with those of NIDDM before treatment. These data indicated that CPT is effective in lowering glomerular filtration pressure and ameliorating microalbuminuria in the normotensive early NIDDM.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Captopril; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Humans; Male; Matched-Pair Analysis; Middle Aged; Prostaglandins; Renal Plasma Flow; Thromboxane B2

We studied the effect of a thromboxane A2 (TXA2) dual blocker KDI-792 on skin blood flow as well as on the peripheral nerve function of nine diabetics with neuropathy. After administration of KDI-792, there was no change in urinary TXB2; however, urinary 6-keto-prostaglandin (PG) F1 alpha increased significantly. Nerve conduction velocity (NCV) and vibration perception threshold (VT) in the four extremities improved significantly, as did deep skin temperature and skin blood flow. The degree of improvement in sensory NCV in the lower extremities correlated significantly with that of deep skin temperature in the toes and the degree of improvement of VT in the lower extremities correlated well with that of deep skin temperature in the soles and of skin blood flow in the toes. Based on these findings, treatment of diabetic neuropathy with a TXA2 dual blocker appears to increase PGI2 production, improving blood flow, and resulting in improvement of nerve functions.

Topics: 6-Ketoprostaglandin F1 alpha; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Enzyme Inhibitors; Extremities; Female; Humans; Male; Middle Aged; Neural Conduction; Perception; Pyridines; Pyrrolidines; Skin; Skin Temperature; Thromboxane A2; Thromboxane B2; Toes; Vibration

Increased platelet aggregability has been shown in hypercholesterolemia, and stirring-induced spontaneous aggregation in whole blood is increased in insulin-dependent diabetes mellitus (DM). We have determined spontaneous aggregation in citrated (10 mM) whole blood, from 27 primary dyslipidemic patients (DYS; 14F, 13M), 16 male non-insulin-dependent DM (NIDDM) patients, and 17 normolipidemic controls (N; 6F, 11M), using platelet counting to quantify aggregation. Spontaneous aggregation was significantly higher, both in the female DYS group (median 30% [interquartile range 25,50], P < 0.005) and the NIDDM group (33% [25,41], P < 0.005), than in the N group (17% [12,27]), but did not differ significantly in the male DYS group (23% [10,33]). Similar results were obtained in the presence of indomethacin (25 mumol/l) to prevent artefactual thromboxane (TX) A2 formation, indicating that increased spontaneous aggregation was TXA2-independent. Interestingly, increased spontaneous aggregation appeared to be independent of serum cholesterol and triglyceride concentrations, as well as age and sex per se. We conclude that spontaneous platelet aggregation was increased both in female primary dyslipidemic patients and NIDDM patients, but not in male DYS patients. The clinical significance of increased spontaneous platelet aggregability is that it may favour shear-induced aggregation which may occur at critical arterial stenoses in vivo leading to thrombus formation.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Hematocrit; Humans; Hyperlipoproteinemia Type II; Male; Platelet Aggregation; Platelet Count; Sex Factors; Thromboxane B2

In uterine tissue obtained from castrated control and non-insulin dependent diabetic (NIDDM) rats, eicosanoid production and its regulation by glucose levels and by the activity of phospholipase A2 (PLA2) was assessed. Basal outputs of prostaglandins (PGs) PGE2, PGE1, PGF2 alpha, 6-keto-PGF1 alpha (indicating the production of prostacyclin), thromboxane B2 (TXB2) (indicating the generation of TXA2) and leukotriene B4 (LTB4) were similar in control and NIDDM uterine preparations as assessed by RIA. When uterine conversion of labelled arachidonate into different prostanoids was evaluated, generation of 6-keto-PGF1 alpha, PGE2 and PGF2 alpha was similar in control and NIDDM uterine tissue, while TXB2 production was higher in the diabetic group. Moreover, when control tissue was incubated in the presence of elevated concentrations of glucose (22 mM) and compared to control tissue incubated in concentrations of glucose 11 mM, similar generation of 6-keto-PGF1 alpha, PGE2 and PGF2 alpha was observed, and higher concentrations of TXB2 were found, similar to those observed in diabetic uterine tissue. When NIDDM uterine tissue was incubated in the presence of glucose 22 mM, no difference in any prostanoid evaluated was observed when compared to values obtained in the presence of glucose 11 mM. In this work we have observed in NIDDM uterine tissue a normal TXA2 production when evaluated by RIA from endogenous arachidonic acid (AA) and a higher TXA2 generation from exogenous labelled AA. In addition PLA2 activity was found diminished in the NIDDM uteri in comparison to control uteri. A role of the diminished PLA2 as a protective mechanism that avoids TXA2 overproduction in uterine tissue from NIDDM rats is discussed.

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Animals; Arachidonic Acid; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dinoprost; Dinoprostone; Eicosanoids; Female; Leukotriene B4; Ovariectomy; Phospholipases A; Phospholipases A2; Rats; Rats, Wistar; Thromboxane B2; Uterus

To evaluate platelet activity in patients with non-insulin-dependent diabetes mellitus (NIDDM), we measured the mean platelet volume (MPV) and 24-hour urinary excretion of 11-dehydro-thromboxane B2 (11-dTXB2) and 6-keto-prostaglandin F1 alpha (6-kPGF1 alpha), stable metabolites of thromboxane A2 and prostacyclin, respectively. The MPV of the 103 subjects in the NIDDM group were 10.72 +/- 0.82 fl for males and 10.52 +/- 1.01 fl for females (mean +/- SD), significantly higher than those of normal controls (9.95 +/- 0.75 fl for males and 9.84 +/- 0.72 fl for females). The MPV of patients with NIDDM showed positive correlations with fasting plasma glucose level and HbA1c (r = 0.234, P < 0.05; r = 0.267, P < 0.01, respectively). The urinary excretion of 11-dTXB2 was greater in the NIDDM group (7.58 +/- 4.42 micrograms/day for males and 5.65 +/- 2.38 micrograms/day for females) than in the normal controls (4.61 +/- 2.31 and 3.83 +/- 1.60, respectively), suggesting that the synthesis of thromboxane A2 by platelets may be accelerated in vivo in patients with NIDDM. The urinary 6-kPGF1 alpha was not different between the NIDDM group and normal controls among the males, but was greater in the NIDDM group among the females. As MPV showed a positive correlation (r = 0.364, P < 0.05) with urinary excretion of 11-dTXB2, MPV may be related to platelet activity. These findings suggest that the platelets of patients with NIDDM may be in a hyperactive state.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Blood Platelets; Case-Control Studies; Cell Size; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Platelet Count; Thromboxane B2

The dynamic changes of 15 parameters (divided into 6 sections in this study) relating to metabolism, platelet function, blood coagulation and hemorrheologic situation under acute exercise loading with the intensity of VO2 max 60% were observed in noninsulin dependent diabetes mellitus (NIDDM) patients. The advantage, safety and feasibility of exercise therapy were discussed.

Topics: Adult; Antithrombin III; beta-Thromboglobulin; Blood Glucose; Diabetes Mellitus, Type 2; Exercise; Female; Humans; Male; Middle Aged; Thromboxane B2

To investigate the possible relevance of free radicals and prostanoids to the mode of initiation and/or evolution of microangiopathy in diabetes mellitus, we measured serum lipid peroxides (LPO), an accepted index of intravascular free radicals, and plasma 11-dehydrothromboxane B2 (11-dehydro-TXB2), a stable metabolite of vasoactive thromboxane A2 released from platelets, in 95 patients with normolipidemic type 2 (non-insulin-dependent) diabetes mellitus at different stages of the disease. In general, either LPO or 11-dehydro-TXB2 was significantly greater in the patients, as a group, than in the matched controls (3.82 vs. 2.65 nmol/ml, P < 0.01 for LPO; and 17.3 vs. 5.8 pg/ml, P < 0.01 for 11-dehydro-TXB2). In patients, both LPO and 11-dehydro-TXB2 increased according to the severity of their diabetic retinopathy. A highly significant positive correlation existed between the LPO values and 11-dehydro-TXB2 in the patients (r = 0.64, P < 0.0001), while there was no such relationship in the controls (r = 0.18, P = NS). No difference in serum levels of apolipoproteins A-I, A-II, B, C-II, C-III, or E was observed between the patients and controls. Short-term glycemic control (25 cal/kg of standardized body weight/day, for 8 weeks) resulted in a small but significant reduction in LPO (4.2 vs. 4.6 nmol/ml, control; P < 0.05) without alteration in 11-dehydro-TXB2. There was a tendency towards deterioration in LPO according to the improvement in glycemic control. These results appear consistent with the view that, in addition to LPO, the release of TXA2 from activated platelet in the human circulation could be an important factor for the initiation and/or evolution of microangiopathy in diabetic patients even when they are not apparently hyperlipidemic. Further, the results of the present study emphasize the notion that more tight control of serum lipids is worthy of serious consideration in preventing the advance of diabetic microangiopathy.

Topics: Aged; Apolipoproteins; Biomarkers; Blood Glucose; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Female; Free Radicals; Glycated Hemoglobin; Humans; Lipid Peroxidation; Lipid Peroxides; Male; Middle Aged; Reference Values; Thromboxane B2; Triglycerides

To evaluate whether improvement of metabolic control or changes in fatty acid composition of serum lipids may alter thromboxane (TXB2) formation and platelet function we followed up 25 newly diagnosed type 2 diabetics without angiopathy for about 6 months. Improvement of metabolic control was associated with significant decrease in total cholesterol (C), HDL-C, LDL-C, triglycerides (TG) and ratios of total C/HDL-C and LDL-C/HDL-C, respectively. Palmitic acid of TG and phospholipids decreased significantly whereas linoleic acid increased in the two serum lipids. The ADP-induced platelet aggregability and sensitivity were not altered. There was even no effect on TXB2 synthesis capacity of clotting whole blood during 6 months of treatment. Platelet aggregability and TXB2 formation were not correlated to the degree of metabolic control, nor was there any correlation to serum lipids and their fatty acid composition.

Topics: Adult; Diabetes Mellitus, Type 2; Fatty Acids; Humans; Lipids; Middle Aged; Platelet Aggregation; Thromboxane B2

Diabetic individuals frequently have platelet hyperaggregability and increased thromboxane (TXB2) production. To evaluate whether improvement of metabolic control or changes in fatty acid composition of serum lipids might alter thromboxane (TXB2) formation and platelet function, we followed up 25 newly diagnosed type 2 diabetics without angiopathy for about 6 months. Improvement of metabolic control (HbA1, fell from 12.0 +/- 0.3 to 9.0 +/- 0.3%; p less than 0.01) was associated with significant decrease in total cholesterol, triglycerides, and ratios of total cholesterol/HDL-cholesterol and LDL-cholesterol/HDL-cholesterol. Palmitic acid of phospholipids decreased significantly, whereas eicosapentaenoic acid increased. Regardless of this, the ADP-induced platelet aggregability and sensitivity were not altered. There was no effect whatever on the TXB2 synthesis capacity of clotting whole blood (204.9 +/- 25.0 vs 222.8 +/- 32.0 ng/ml) over 6 months of treatment. Platelet aggregability and TXB2 formation were not correlated to the degree of metabolic control, nor were there any correlations to serum lipids and their fatty acid composition. Thus, we are tempted to speculate that glucose metabolism in diabetes itself does not affect platelet aggregation or TXB2 formation in type 2 diabetes mellitus.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Diet, Diabetic; Fatty Acids; Female; Glycated Hemoglobin; Humans; Lipids; Male; Middle Aged; Platelet Aggregation; Thromboxane B2

Recently the beneficial effects of captopril (angiotensin-converting-enzyme inhibitor) on diabetic nephropathy, especially proteinuria, have been reported by some investigators. The mechanism whereby proteinuria is reduced, however, have not been clarified yet. The present study was undertaken to evaluate the effects of captopril on urinary albumin excretion in relation to urinary prostaglandins (PGs) excretion in patients with non-insulin-dependent diabetes mellitus (NIDDM). Captopril (37.5 mg/day) was orally administered to 13 diabetic patients for an eight-week period. A single administration of captopril (12.5 mg) was performed in the same patients. The spot urine samples were collected in the early morning and 2 hr after the single administration of captopril. The albumin index (mg/gram-creatinine) was markedly decreased in eight patients (Group A) within four weeks, but no decrease was found in five patients (Group B). Furthermore, in Group A, by the single administration of captopril urinary excretions of 6-keto-PCF1 alpha (a stable metabolite of PGI2) and PGE2 were significantly (p less than 0.05) increased while urinary TXB2 (a stable metabolite of TXA2) excretion did not change significantly. The urinary 6-keto-PGF1 alpha/TXB2 ratio, which is significantly (p less than 0.05) low in diabetic patients was significantly (p less than 0.01) increased up to the normal value in Group A. In Group B, however, there were no significant changes in urinary PGs excretion. These results suggest that captopril enhances the production of intrarenal vasodilatory PGs such as PGI2 and PGE2, which may be deeply involved in the reduction of intraglomerular capillary pressure and urinary protein excretion in diabetic patients.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Humans; Male; Middle Aged; Prostaglandins; Thromboxane B2

A decrease in the vitamin E content of human diabetic platelets is closely associated with the accelerated platelet aggregation and platelet prostaglandin metabolism seen in patients with diabetes mellitus. We investigated the effect of vitamin E supplementation on these abnormalities of physiological function and prostaglandin metabolism in 14 non-insulin dependent diabetics with proliferative retinopathy. ADP-induced platelet aggregation was inhibited in vitro by the addition of vitamin E in a dose-dependent manner. However, in lower concentrations considered to be physiological doses in vivo, significantly greater inhibition was observed in diabetic platelets than in the control platelets. Next, alpha-tocopheryl nicotinate was administered to diabetics at a daily dose of 600 mg. The platelet vitamin E content was restored to control levels in 13 of the 14 patients after 2-4 weeks of daily administration. The ADP-induced platelet aggregation rate, platelet thromboxane B2 (TXB2, a stable metabolite of TXA2, a vasoconstrictor production, and plasma TXB2 level were low in all 14 diabetics. In contrast, plasma 6-keto-PGF 1 alpha (a stable metabolite of PGI2, a vasodilator) was significantly increased and therefore the 6-keto-PGF 1 alpha/TXB2 ratio in plasma was restored to within normal limits. These results indicate that vitamin E may improve platelet function and prostaglandin metabolism in diabetes mellitus and may be able to provide further beneficial effects in relation to the development of diabetic vascular complications.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Blood Glucose; Blood Platelets; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Reference Values; Thromboxane B2; Time Factors; Vitamin E

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

The effect of EPA enriched marine oil on platelet function in 12 cases of hypertension, 15 cases of diabetes and 20 cases of coronary heart disease is reported. The result of our study showed that there was platelet hyperfunction of various degrees in patients with those three kinds of diseases. The murine oil had an effect of inhibition, which were manifested by the prolongation on bleeding time, and decreased on platelet adhesion and aggregation. TxB2 in plasma was reduced, while 6-keto-PGF increased. There was no influence of EPA enriched fish oil on blood sugar and liver or kidney function. The authors concluded that platelet hyperfunction is an important element in the development of cardio vascular and cerebro vascular complications and increases the mortality rates in these diseases. Treatment with such a drug has beneficial effect with clinical improvement.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Bleeding Time; Blood Coagulation; Blood Platelets; Coronary Disease; Diabetes Mellitus, Type 2; Eicosapentaenoic Acid; Female; Fish Oils; Humans; Hypertension; Male; Middle Aged; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane B2

The present study was designed to determine urinary excretion of kallikrein(KAL)-kinin as well as prostaglandin (PG) E2, TXB2 and 2,3-dinor-TXB2, a major urinary metabolite of TXA2 synthesized in platelets, by specific RIAs in patients with diabetes mellitus (DM). KAL or kinin excretion in 26 type II DM did not differ from control values obtained in 18 age-matched healthy subjects (C), although DM with HbA1 greater than 11% excreted less KAL. Urinary PGE2 excretion (7.6 +/- 2.8 ng/mg creatinine, mean +/- SE) was significantly lower in DM compared to C (17.5 +/- 3.9, p less than 0.05), while DM excreted more TXB2 (0.57 +/- 0.09, p less than 0.01) and 2,3-dinor-TXB2 (0.56 +/- 0.12, N.S.) than C (0.19 +/- 0.02 or 0.33 +/- 0.01). DM with or without mild proteinuria demonstrated lower PGE2, but higher TXB2 and 2,3-dinor-TXB2 excretion. A positive correlation of TXB2/2,3-dinor-TXB2 with proteinuria was observed in this group. However, in DM with massive proteinuria over 500 micrograms/mg creatinine, TXB2 and 2,3-dinor-TXB2 excretion decreased to levels almost identical to C. As a whole, a ratio of TXB2 to PGE2 or 2,3-dinor-TXB2 in DM was significantly higher than in C. The results suggest that a relative preponderance of TXB2 to 2,3-dinor-TXB2 may indicate an augmented renal, in addition to platelet, TXA2 synthesis. An excessive vasoconstrictive and proaggregatory TXA2 renal synthesis, concomitant with a decrease in vasodilatory and antiaggregatory PGE2, may have profound effects on renal functions such as protein excretion in DM.

Topics: Adult; Aged; Blood Pressure; Diabetes Mellitus, Type 2; Dinoprostone; Eicosanoids; Esterases; Female; Humans; Kallikreins; Kidney; Kinins; Male; Middle Aged; Thromboxane A2; Thromboxane B2

It has been suggested that platelet hyperreactivity in patients with diabetes mellitus is associated with increased platelet production of thromboxane. We therefore compared the excretion of a thromboxane metabolite and platelet function in 50 patients with Type II diabetes mellitus who had normal renal function and clinical evidence of macrovascular disease and in 32 healthy controls. The mean (+/- SD) excretion rate of urinary 11-dehydro-thromboxane B2 was significantly higher in the patients than in the controls (5.94 +/- 3.68 vs. 1.50 +/- 0.79 nmol per day; P less than 0.001), irrespective of the type of macrovascular complication. Tight metabolic control achieved with insulin therapy reduced the levels of 11-dehydro-thromboxane B2 by approximately 50 percent. The fractional conversion of exogenous thromboxane B2 (infused at a rate of 4.5, 45.3, or 226.4 fmol per kilogram of body weight per second) to urinary 11-dehydro-thromboxane B2 was assessed in four patients, in whom it averaged 5.4 +/- 0.1 percent; this value did not differ from that measured in healthy subjects. Aspirin in low doses (50 mg per day for seven days) reduced urinary excretion of the metabolite by approximately 80 percent in four patients. The fact that thromboxane biosynthesis recovered over the following 10 days was consistent with a platelet origin of the urinary metabolite.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Blood Platelets; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Platelet Aggregation; Thromboxane A2; Thromboxane B2; Thromboxanes

Twelve well-controlled, type II diabetic patients without hypertension and advanced diabetic complications and 12 age-matched healthy control subjects were treated for 4 days with captopril 25 mg three times daily. The pretreatment values of plasma renin activity, plasma aldosterone, urinary 6-keto prostaglandin F1 alpha and thromboxane B2 were similar in both groups. Urinary prostaglandin E2 was significantly reduced in diabetics. After captopril plasma renin activity increased significantly in the diabetics and control subjects. Plasma aldosterone was not significantly decreased in both groups. Urinary prostaglandin E2 increased significantly in both diabetic and control groups. Other measured prostaglandins remained unchanged. After captopril systolic blood pressure decreased significantly in diabetics and not significantly in the control group. The results indicate that captopril was an effective drug for lowering blood pressure in diabetic patients, too. It is possible that the antihypertensive effect of captopril in diabetics could be due at least partly to prostaglandin E2.

Topics: 6-Ketoprostaglandin F1 alpha; Aldosterone; Blood Pressure; Captopril; Diabetes Mellitus, Type 2; Dinoprostone; Female; Humans; Male; Middle Aged; Renin; Renin-Angiotensin System; Thromboxane B2

In the present study the effects of a short term intensive glycaemic control obtained with subcutaneous insulin therapy on lipids and apoprotein levels, platelet aggregation, platelet sensitivity to prostacyclin and platelet thromboxane production were investigated in 20 patients with type 2 diabetes and vascular disease. In 11 out of the 20 patients there was a significant improvement of glycaemic control (fructosamine reduction). Only with tight improvement of glycaemic control there was significant change in the concentration of ADP and collagen required to produce 50% of the maximum aggregation wave response, in the responsiveness of platelet to PGI2 and in the TxB2 synthesis. Lower Apo B levels were also shown in the tight control group suggesting that Apo B changes may have influenced platelet aggregation and thromboxane synthesis.

Topics: Adult; Apolipoproteins; Biomarkers; Blood Glucose; Blood Platelets; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Fructosamine; Glycated Hemoglobin; Hexosamines; Humans; In Vitro Techniques; Insulin; Lipoproteins, HDL; Male; Middle Aged; Platelet Aggregation; Thromboxane B2

A study was conducted to determine the effects of glibenclamide on serum lipoproteins, apolipoproteins, thromboxane (TXA2), prostacyclin (PGI2), and beta-thromboglobulin (B-TGL) in patients with newly diagnosed non-insulin-dependent diabetes mellitus (NIDDM). In 20 NIDDM patients, aged 34 to 67 (mean, 53.6) years, without clinical signs of atherosclerotic disease and whose blood sugar level was over 140 mg/dl after four weeks of dietary treatment, fasting blood samples were taken before the beginning of the trial, after four weeks of dietary treatment, and after four and eight weeks of combined dietary and glibenclamide treatment. Pretrial levels of total serum cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) in the diabetic patients did not differ from those in nondiabetic controls, whereas high-density lipoprotein cholesterol (HDL-C) levels and the percentage of TC bound to HDL (HDL-C%) were significantly lower in the patients than in controls. After combined dietary and glibenclamide treatment and the normalization of blood sugar, both HDL-C (mg/dl) levels and HDL-C% levels increased significantly. TC, TG, and LDL-C levels decreased. Levels of apolipoproteins A1 and A2 rose and apolipoprotein B fell, but differences were not significant. TXB2 and 6-keto-PGF1-alpha (the inert metabolites of TXA2 and PGI2) and B-TGL were determined by radioimmunoassay. TXB2 and B-TGL levels decreased significantly after glibenclamide administration, indicating attenuation of platelet aggregation. No changes in PGI2 were observed. The results demonstrate the favorable effect of glibenclamide on lipoproteins and apolipoproteins in NIDDM patients, especially in increasing HDL-C levels and HDL-C%, and in attenuating platelet aggregation as indicated by reduction of TXB2 and B-TGL.

Topics: Adult; Aged; Apolipoproteins; Apolipoproteins A; Apolipoproteins B; beta-Thromboglobulin; Blood Glucose; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Epoprostenol; Female; Glyburide; Humans; Lipids; Lipoproteins; Male; Middle Aged; Thromboxane B2; Thromboxanes

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

Abnormalities of platelet aggregation, and increased levels of lipid peroxides and denatured proteins have been implicated in the pathogenesis of diabetic microangiopathy. Seventeen non-insulin dependent diabetics (mean age 65.7) on established sulphonylurea therapy were converted to an equivalent dose of gliclazide. They were studied at baseline and intervals to 36 weeks. Thromboxane B2 (TXB2) and beta thromboglobulin (beta TG) were measured by radioimmunoassay. Lipid peroxides were measured as total diene conjugates (DC) by scanning UV spectrophotometry and thiobarbituric acid reactivity (TBA) by absorbance at 532 nm. Oxidation products of proteins were represented by fluorescence/UV ratio of immunoglobulin G (*IgG) separated from serum by HPLC. Glycaemic control remained stable throughout the study. TXB2 fell from 734 +/- 233 ng/l at 0 weeks to 488 +/- 155 at 36 weeks, p less than 0.001 and beta TG from 120 +/- 70 ng/ml to 48 +/- 18 at 24 weeks, p less than 0.005. Lipid peroxides fell between 0 and 36 weeks; DC from 0.71 +/- 0.28 to 0.32 +/- 0.09, p less than 0.001 and TBA from 29.6 +/- 22.4 to 4.0 +/- 2.2, p less than 0.001. Fluorescent IgG ratio fell from 1.44 +/- 0.36 to 0.32 +/- 0.07, p less than 0.001. This data provides evidence for a specific action of gliclazide on thromboxane synthesis and platelet aggregation. This is independent of glycaemic control and may in part be mediated by the observed fall in lipid peroxides.

Topics: Aged; Blood Proteins; Diabetes Mellitus, Type 2; Female; Fructosamine; Gliclazide; Glyburide; Glycated Hemoglobin; Hexosamines; Humans; Immunoglobulin G; Lipid Peroxides; Male; Platelet Aggregation; Sulfonylurea Compounds; Thromboxane B2

The relationship between diabetic neuropathy on the one hand and microangiopathy and arteriosclerosis on the other was studied by determining plasma 6-keto-prostaglandin F1 alpha (PGF1 alpha) and plasma thromboxane B2 (TXB2) in diabetics with neuropathy. The subjects were 13 patients with insulin independent diabetes mellitus with polyneuropathy (DN+ group), 9 cases which had no neuropathy (DN- group) and 6 control cases. The patients with severe retinopathy, nephropathy and hypertension were excluded. Plasma 6-keto-PGF1 alpha and plasma TXB2 concentration were determined by radioimmunoassay. The motor neuron conduction velocity (M.C.V.) was measured through the tibial nerve in all diabetics. Plasma 6-keto-PGF1 alpha was 116.3 +/- 4.2 pg/ml (mean +/- SE) in the DN+ group and 139.9 +/- 3.0 in the DN- group, each group showing a significant fall over the control with 150.8 +/- 4.5. Plasma 6-keto-PGF1 alpha in the DN+ group showed a significant decrease in comparison with that in the DN- group. As to plasma TXB2, there was no significant difference among the three groups. The M.C.V. fell off significantly in the DN+ group with 52.9 +/- 3.2 m/sec. Furthermore, a significant positive correlation was observed between M.C.V. and plasma 6-keto-PGF1 alpha. The following is the summary of these results. A decrease in plasma 6-keto-PGF1 alpha was observed in diabetics with polyneuropathy. A decrease in the production of prostacyclin (PGI2) due to impairment of vascular endothelium in the nerve tissue was surmised. The decrease in plasma 6-keto-PGF1 alpha presumably stimulates the activity of platelet agglutination and causes an ischemic change in the nerve tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Humans; Middle Aged; Motor Neurons; Neural Conduction; 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

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Antigens; beta-Thromboglobulin; Blood Platelets; Diabetes Mellitus, Type 2; Endothelium; Factor VIII; Female; Glyburide; Humans; Male; Metformin; Middle Aged; Platelet Aggregation; Thromboxane B2; von Willebrand Factor

Plasma levels of beta-thromboglobin (beta-TH) and of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1-alpha, the stable metabolites of thromboxane A2 and prostacyclin, were determined by radioimmunoassay methods in eight patients with noninsulin-dependent diabetes before and after dietary treatment and after administration of the sulfonylurea drug glibenclamide. Blood examinations were performed when hyperglycemia was detected for the first time, four weeks after a dietary regimen was started, and four and eight weeks after glibenclamide treatment was begun. Drug treatment was instituted because, despite a suitable diet, patients' postprandial blood sugar was higher than 8 mmol/L (145 mg/dl). At the initial examination, elevated TXB2 and beta-TH levels indicating platelet hyperactivity and hyperglycemia were found. TXB2 and beta-TH levels decreased significantly after glibenclamide treatment was started, as did the blood glucose level. There was no change in 6-keto-PGF1-alpha. We interpret these results to indicate that diabetes is associated with hyperactivity of platelet aggregation and that control of blood glucose is important because a lower blood glucose level attenuates platelet hyperactivity. Whether the decrease in platelet hyperactivity is a direct result of the lowered blood sugar or reflects the influence of the drug treatment requires clarification.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Beta-Globulins; beta-Thromboglobulin; Blood Glucose; Blood Platelets; Diabetes Mellitus, Type 2; Female; Glyburide; Humans; Male; Middle Aged; Platelet Aggregation; Radioimmunoassay; 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

Platelet thromboxane B2 production was studied in forty-seven non-insulin-dependent diabetics by incubating platelets with increasing concentrations of arachidonic acid. In comparison with thirty-two healthy subjects, diabetics showed increased thromboxane B2 production at 0.7 mmol/l (mean: 236 pmol/10(8) platelets, SEM 201-277; v. 135, 105-174; P less than 0.05) and at 1.0 mmol/l (673, 613-739; v. 405, 377-486, P less than 0.01) but not at 0.5 mmol/l. Patients were subdivided according to the presence or absence of vascular complications. Patients without microangiopathy showed significantly greater thromboxane B2 production than healthy subjects at all the arachidonic-acid concentrations (P less than 0.02 or less). Patients with microangiopathy had platelet thromboxane production similar to that observed in healthy subjects at all the arachidonic-acid concentrations (P greater than 0.30) but significantly lower than that of non-microangiopathic patients at 0.5 (P less than 0.01) and at 0.7 mmol/l arachidonic acid (P less than 0.05). These results indicate that non-insulin-dependent diabetics have increased production of platelet thromboxane B2 only when they do not have microvascular complications.

Topics: Adult; Aged; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Cholesterol; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Male; Middle Aged; Thromboxane B2; Thromboxanes; Triglycerides

Vitamin E is known to be an inhibitor of platelet prostaglandin production and aggregation. The rate of platelet aggregation induced by adenosine diphosphate was significantly increased in diabetics with proliferative retinopathy, and the enhanced production of thromboxane B2, a stable metabolite of thromboxane A2, was demonstrated in those patients. On the other hand, vitamin E was significantly reduced in platelets obtained from diabetics as compared to age matched control subjects. In addition, it was shown that vitamin E content in platelets examined in diabetic and control subjects inversely correlated with both the rate of platelet aggregation and thromboxane B2 production during aggregation. It is suggested that the reduced vitamin E levels in diabetic platelets can contribute to the mechanisms of the enhanced platelet thromboxane A2 production and aggregation which lead to the development of vascular complications.

Topics: Adenosine Diphosphate; Adult; Blood Platelets; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Female; Humans; Male; Middle Aged; Platelet Aggregation; Thromboxane B2; Vitamin E

Vitamin E is known to be an inhibitor of platelet prostaglandin production and aggregation. The rate of platelet aggregation induced by adenosine diphosphate was significantly increased in diabetics with proliferative retinopathy and the enhanced production of thromboxane B2, a stable metabolite of thromboxane A2, was demonstrated in those patients. On the other hand, vitamin E in platelets was significantly reduced in diabetics compared with age matched controls. In addition, it was shown that vitamin E content in platelets examined in diabetic and control subjects inversely correlated with both the rate of platelet aggregation and thromboxane B2 production during aggregation. It is suggested that the reduced vitamin E levels in diabetic platelets can contribute to the mechanisms of the enhanced platelet thromboxane production and aggregation which relate to the development of vascular complications.

Topics: Blood Platelets; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Middle Aged; Platelet Aggregation; Thromboxane B2; Vitamin E