thromboxane-b2 and Insulin-Resistance

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

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

In the rat, a high-fat (HF) plus fructose (F) diet produces cardiovascular and metabolic alterations that resemble human metabolic syndrome. Prostanoids (PR), cyclo-oxygenase-derived arachidonic acid metabolites, have vasoactive properties and mediate inflammation. The aim of this study was to analyse the effect of a HF+F diet on blood pressure (BP), metabolic parameters and mesenteric vascular bed PR production in male Sprague-Dawley rats. Four groups were studied over 9 weeks (n = 6 each): control (C), standard diet (SD) and tap water to drink; F+SD and 10% w/v F solution to drink; HF 50% (w/w) bovine fat added to SD and tap water; and HFF, both treatments. PR were determined by HPLC. Blood pressure was elevated in all experimental groups. Triglyceridaemia, insulinaemia and HOMA-IR were increased in the F and HF groups. HF+F animals showed elevated glycaemia, insulinaemia, HOMA-IR and triglyceridaemia. F decreased the vasodilator prostanoids PGI2 and PGE2 in the mesenteric vascular bed. Body weight was not significantly altered. In HFF, production of PGE2 , PGF2 alpha and TXB2 was elevated. The increased BP in HF and HFF could be partly attributed to the imbalance in vascular PR production towards vasoconstrictors. On the other hand, this dietary modification could induce inflammation, which would explain the elevation of PGE2 . In the F group, hypertension could be related to decreased vasodilator PRs. The simultaneous administration of HF and F in the rat produces deleterious effects greater than observed when treatments are applied separately.

Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Diet, High-Fat; Fructose; Insulin; Insulin Resistance; Male; Mesenteric Arteries; Metabolic Syndrome; Prostaglandins; Rats; Thromboxane B2; Triglycerides

The work was designed to study levels of serum prostaglandin F1a (6-keto-PGF1a), thromboxane B2, and leukotriene B4 (LTB4)--stable products of cyclooxygenase and lipogenase-catalyzed reactions of arachidonic acid, in patients with metabolic syndrome (MS) differing in glucose homeostasis. It was shown that MS is associated with excess production of anti-inflammatory oxilipines (LTB4) regardless of the presence or absence of insulin resistance. LTB4 are known to influence inflammatory processes due to compensatory synthesis of vasodilating eicosanoids (6-keto-PGF1a) that antagonize vasoconctriction and inflammation. Combination of MS with insulin resistance in patients with elevated LTB4 and 6-keto-PGF1a levels is associated with enhanced synthesis of thromboxane A2 responsible for vasoconstriction, platelet formation, and development of endothelial dysfunction. The study suggests disturbed synthesis of eicosanoids in patients with MS and their important role in pathogenesis of this condition.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Eicosanoids; Female; Humans; Insulin Resistance; Leukotriene B4; Male; Metabolic Syndrome; Middle Aged; Thromboxane B2; Young Adult

Recent studies indicate that not all diabetic subjects benefit from aspirin therapy. Our objective is to characterize diabetic subjects with aspirin resistance using urine thromboxane, and VerifyNow measures. Our results suggest that cardiovascular disease, microalbuminuria, poor diabetes control, and increased waist circumference help identify aspirin resistance in diabetes.

Topics: Albuminuria; Aspirin; Cohort Studies; Diabetic Angiopathies; Drug Resistance; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Male; Middle Aged; Nephelometry and Turbidimetry; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane B2; Waist Circumference

We tested the hypothesis that insulin resistance, per se, contributes to increased platelet activation in obesity, independently of underlying inflammation.. Obesity, insulin resistance, and atherosclerosis are closely linked phenomena associated with low-grade inflammation. Obesity is associated with persistent platelet activation in otherwise healthy women.. We performed a cross-sectional study in 40 obese and 20 non-obese healthy women using urinary thromboxane metabolite excretion as a non-invasive index of platelet activation. An index of insulin sensitivity, S(I), and plasma adiponectin, C-reactive protein (CRP), and CD40 ligand (CD40L) levels were measured.. Obese women had significantly (p < 0.0001) higher 11-dehydro-thromboxane B2 (11-dehydro-TXB2) excretion (median 718 vs. 211 pg/mg creatinine), CRP (1.13 vs. 0.48 mg/l), and CD40L levels (4.45 vs. 0.90 ng/ml) than controls. Obese women had lower S(I) (median 2.51 vs. 5.0 10(4) min(-1)/[microU/ml], p < 0.002) and adiponectin (6.3 vs. 10 microg/ml, p < 0.01) than control subjects. On multiple regression analysis, waist-to-hip ratio (beta = 0.27, p < 0.05) and S(I) (beta = -0.72, p < 0.04) predicted 11-dehydro-TXB2 excretion rate, independently of adiponectin, CRP, CD40L, and lipid patterns. In order to investigate the cause-effect relationship of these associations, we examined the effects of a 12-week weight loss program or a 3-week pioglitazone treatment on urinary 11-dehydro-TXB2 in 10 women with impaired S(I) and visceral obesity. Successful weight loss (0.6 kg loss/week) achieved in 5 subjects was associated with increased S(I) (+92%) and decreased CD40L (-27%), CRP (-37%), and 11-dehydro-TXB2 (-53%) (p < 0.05). Consistently, improvement of insulin sensitivity achieved with pioglitazone significantly decreased urinary 11-dehydro-TXB2 excretion (-43%, p < 0.05) without changes in body weight.. Insulin resistance is a major determinant of platelet activation in female obesity.

Topics: Adult; Cross-Sectional Studies; Female; Humans; Insulin Resistance; Middle Aged; Obesity; Platelet Activation; Thromboxane B2

To investigate insulin resistance and the effects of intravenous acute saline load on renal production of prostaglandin I(2) (PGI(2)) and thromboxane A(2) (TXA(2)) in salt-sensitive hypertensive patients.. The 24-hour excretion of urinary 6-keto-prostaglandin F (PGF) 1alpha and thromboxane B(2) were measured before and after intravenous acute saline load in 53 hypertensive patients whose salt sensitivity had been determined. Oral glucose tolerance test and insulin release test were performed in all the subjects.. after intravenous acute saline load, the 24-hour excretions of urinary 6-keto PGF 1alpha were significantly lower in salt-sensitive (SS) hypertensive patients than that in non-salt-sensitive (NSS) ones (316+/-57 pg/min vs 371+/-68 pg/min, P<0.01), and the decrease from baseline was much greater in SS group than that in NSS group (197+/-99 pg/min vs 136+/-101 pg/min, P<0.01). Both 24 hour urinary excretion of TXA(2) and the increase in urinary excretion of TXA(2) were significantly greater in SS hypertensive patients than those in NSS ones after salt loading (394+/-32 pg/min vs 359+/-44 pg/min, P<0.01, and 80+/-47 pg/min vs 47+/-45 pg/min, P<0.01, respectively). The plasma glucose and insulin concentrations in every time point were much higher in SS hypertensive subjects than that in NSS ones, and the former group had lower insulin sensitivity index than the latter (0.013+/-0.003 vs 0.018+/-0.004, P<0.01). Saline load produces significantly different effects on renal production of PGI(2) and TXA(2) in SS and NSS hypertensive patients, and these changes may be related to the pathophysiology of SS hypertensive patients after acute salt loading. Insulin resistance is greater in SS hypertensive patients than in NSS ones.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Female; Humans; Hypertension; Injections, Intravenous; Insulin Resistance; Kidney; Male; Middle Aged; Sodium Chloride; Thromboxane A2; Thromboxane B2