thromboxane-a2 and Diabetes-Mellitus--Type-1

Platelet poor plasma thromboxane and prostacyclin levels and the quantity of metabolic control, altogether with vascular complications were evaluated in 55 children diabetes mellitus. The control group consisted of 33 healthy children of the similar age. Thromboxane levels remained unchanged in diabetics, while prostacyclin proved to be significantly decreased, which resulted in greater thromboxane/prostacyclin ratio. No meaningful differences were found according to the presence or absence of vascular complications in this group of diabetics. A positive correlation could have been detected between glycosylated haemoglobin and thromboxane levels, while a negative one between glycosylated haemoglobin and prostacyclin levels. The alterations of prostaglandin metabolism may be regarded as a consequence of diabetic metabolic changes, rather than of vascular complications. Disturbed prostaglandin metabolism in diabetic children might have a role in the pathogenesis of vascular complications.

Topics: Blood Glucose; Child; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Epoprostenol; Glycated Hemoglobin; Humans; Prostaglandins F; Thromboxane A2

This report describes, at least in part, the role of prostaglandin and cyclic nucleotide metabolism in the etiology of the vascular disease associated with diabetes mellitus. Alterations in this metabolism seem associated with induction of platelet aggregation leads to microthromboses leads to microangiopathy sequences that are subtle but inexorable over a long period of time. Prostaglandins are generally elevated in blood from patients having frank signs of diabetic retinopathy when compared with nondiabetic subjects. Prostaglandin concentration remained elevated in diabetic retinopathy patients receiving indomethacin. We formed, therefore, the working hypothesis--yet to be fully tested either in patients or animal models with and without indomethacin treatment--that the increased prostacyclin (synthesized by endothelial microsomes) and cyclic-AMP production, both of which favor prevention of platelet aggregation, accompany the increased concentration of one or more of the prostaglandin E and F compounds. Concurrently, there may be an accompanying reduction of thromboxane A2 (synthesized by platelet microsomes) and cyclic-GMP (both of which favor platelet aggregation) production in the diabetic patients. The elevated prostaglandin in the diabetic patients not receiving indomethacin could possibly be directed toward slowing but not preventing the progression of the complex disease process in diabetes.

Topics: Alprostadil; Aspirin; Blood Platelets; Calcimycin; Collagen; Cyclic AMP; Cyclic GMP; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Dinoprost; Dinoprostone; Humans; Indomethacin; Models, Biological; Platelet Aggregation; Prostaglandins; Prostaglandins E; Prostaglandins F; Thromboxane A2

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

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

Vitamin E deficiency is associated with increased platelet aggregation, which can be normalized through vitamin E supplementation. In diabetes, increased platelet thromboxane A2 (TXA2) production is correlated with decreased platelet vitamin E content. We therefore investigated the effect of 400 mg DL-alpha-tocopherol acetate daily for 4 wk on ADP- and collagen-induced platelet aggregation and platelet TXA2 production in 22 type I (insulin-dependent) diabetic patients without macroangiopathy and with no or only minimal microangiopathy by a double-blind placebo-controlled crossover study. Platelet aggregation was induced in platelet-rich plasma by two or three different concentrations of ADP and collagen. TXA2 was measured by the stable spontaneous breakdown product thromboxane B2 by a specific radioimmunoassay. Whereas metabolic control remained unchanged during the study period, platelet TXA2 production was significantly (P less than .05 and P less than .01) reduced at each ADP concentration and at two of three collagen concentrations. Because increased TXA2 production of diabetic platelets is thought to play an important pathogenetic role in diabetic angiopathy, we conclude that vitamin E treatment could be beneficial with respect to platelet-vessel-wall interaction and thus might be promising for the prevention of diabetic angiopathy.

Topics: Adenosine Diphosphate; Adult; Blood Platelets; Clinical Trials as Topic; Collagen; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Humans; Male; Platelet Aggregation; Reference Values; Thromboxane A2; Vitamin E

A randomised trial of the effects of 15 gm per day of a fish oil supplement (MaxEPA) on blood lipids, haemostatic variables (including platelet function) and albuminuria was undertaken in 41 insulin dependent diabetics. Compared with the control group there was a significant reduction in thromboxane production by platelets stimulated by collagen in vitro in the group who took the fish oil supplement. The extent of platelet aggregation was not altered but the lag phase before aggregation was prolonged. There were also statistically significant increases in plasma LDL cholesterol, fibrinogen and clotting factor X in the group who took the fish oil supplement. No other significant differences were noted.

Topics: Administration, Oral; Adult; Albuminuria; Blood Coagulation Tests; Blood Platelets; Diabetes Mellitus, Type 1; Diet, Diabetic; Docosahexaenoic Acids; Drug Combinations; Eicosapentaenoic Acid; Erythrocyte Membrane; Fatty Acids, Unsaturated; Female; Fish Oils; Hemostasis; Humans; Middle Aged; Platelet Function Tests; Thromboxane A2

Platelet activation is persistently enhanced, and its inhibition by low-dose aspirin is impaired in type 2 diabetes mellitus. We investigated in vivo thromboxane (TX) and prostacyclin (PGI2) biosynthesis and their determinants, as well as aspirin responsiveness, in young adult subjects with type 1 diabetes mellitus (T1DM) without overt cardiovascular disease and stable glycemic control. The biosynthesis of TXA2 was persistently increased in subjects with T1DM versus matched healthy subjects, with females showing higher urinary TX metabolite (TXM) excretion than male subjects with T1DM. Microalbuminuria and urinary 8-iso-PGF2α, an index of in vivo oxidative stress, independently predicted TXM excretion in T1DM. No homeostatic increase in PGI2 biosynthesis was detected. Platelet COX-1 suppression by low-dose aspirin and the kinetics of its recovery after drug withdrawal were similar in patients and control subjects and were unaffected by glucose variability. We conclude that patients with T1DM and stable glycemic control display enhanced platelet activation correlating with female sex and microvascular and oxidative damages. Moreover, aspirin responsiveness is unimpaired in T1DM, suggesting that the metabolic disturbance per se is unrelated to altered pharmacodynamics. The efficacy and safety of low-dose aspirin in T1DM warrant further clinical investigation.

Topics: Adult; Albuminuria; Aspirin; Blood Glucose; Cross-Sectional Studies; Cyclooxygenase 1; Diabetes Mellitus, Type 1; Dinoprost; Epoprostenol; Female; Humans; Male; Matched-Pair Analysis; Microvessels; Middle Aged; Oxidative Stress; Platelet Activation; Platelet Aggregation Inhibitors; Sex Factors; Thromboxane A2

Topics: Aspirin; Diabetes Mellitus, Type 1; Epoprostenol; Female; Humans; Male; Platelet Activation; Platelet Aggregation Inhibitors; Thromboxane A2

Although aspirin treatment is useful in reducing ischaemic events in diabetic patients, recent studies suggest that it is less effective when compared with non-diabetics (ND). We sought to evaluate COX-1 sensitivity and thromboxane A(2) (TxA(2)) production in type 1 (T1DM) and type 2 diabetic (T2DM) patients under chronic aspirin treatment, and also evaluate the association between thromboxane A(2) (TxA(2)) production and markers of inflammation and metabolic control, such as high-sensitivity C-reactive protein, fasting blood glucose, and haemoglobin A1c (HbA1c).. Agonist-induced platelet aggregation (PA) and TxB(2), a stable metabolite of TxA(2), production, serum TxB(2), and platelet COX-1 and COX-2 expression were studied in T2DM patients, T1DM patients, and high-risk ND subjects, all receiving a low dose of aspirin. TxB(2) formation was studied in platelets treated in vitro with aspirin alone or with a COX-2 inhibitor (NS-398). PA, collagen-induced TxB(2) production, and serum TxB(2) were higher in T1DM and T2DM patients than in ND subjects. TxB(2) production was reduced in diabetic patients by in vitro treatment with aspirin. COX-2 was expressed in all diabetic patients but only in 46% of ND patients. In diabetic patients significant correlations were observed between TxB(2) production and both fasting plasma glucose and HbA1c.. COX-1 sensitivity and TxB(2) production is similarly reduced in both T1DM and T2DM patients under chronic aspirin treatment. The association between TxB(2) production and either fasting plasma glucose and HbA1c levels suggests that in diabetic patients hyperglycaemia is a determinant of the reduced platelet sensitivity to aspirin.

Topics: Adult; Aged; Aspirin; Blood Platelets; C-Reactive Protein; Case-Control Studies; Cyclooxygenase 1; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Resistance; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Statistics, Nonparametric; Thromboxane A2

Patients with type 1 diabetes, aged 18 to 42 years, were compared to those aged 11 to 22 years. Activities of endothelial vasoactive factors and endothelial and leukocyte adhesion molecules were studied at different stages of development diabetes complications: nephropathy and retinopathy. The findings reveal role of the vasoactive factors in microangiopathy course.

Topics: Adolescent; Adult; Biomarkers; Child; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; E-Selectin; Endothelin-1; Endothelium, Vascular; Epoprostenol; Humans; Intercellular Adhesion Molecule-1; Microcirculation; Nitric Oxide; Thromboxane A2

16 patients with insulin-dependent diabetes mellitus (IDDM) lasting 8-19 years had pronounced diabetic nephropathy (proteinuria stage), retinopathy (stage I, II or III), disturbed circulation in the lower limbs detected at foot dopplerography. For 3 months these patients received ibustrin (inhibitor of cyclooxigenase, blocker of tromboxane A2 synthesis and platelet aggregation) before renal function underwent positive changes: glomerular filtration rate increased in 13 patients (81%), 24-h proteinuria decreased in 12 patients (75%). Retinal vascular condition improved in 5 of 6 patients with nonproliferative retinopathy and in 2 of 5 patients with preproliferative retinopathy, in 1 and 3 patients stabilization occurred, respectively. In proliferative retinopathy improvement and stabilization were registered in 1 and 3 of 5 patients, respectively. According to feet artery dopplerography the improvement, no changes and moderate aggravation occurred in 10(62%), 3(19%) and 3(19%) of patients, respectively The conclusion is made that ibustrin effectively inhibits progression of IDDM vascular complications, especially at early angiopathy stages.

Topics: Adolescent; Adult; Blood Coagulation; Chronic Disease; Cyclooxygenase Inhibitors; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Drug Evaluation; Foot; Humans; Isoindoles; Middle Aged; Phenylbutyrates; Platelet Aggregation Inhibitors; Thromboxane A2

Prostacyclin and thromboxane A2 are important regulators of kidney blood flow. To examine whether changes in their metabolism could be involved in the nephrotoxicity of cyclosporin, we determined urinary excretion of 6-keto PGF1a and dinor-6-keto PGF1a (prostacyclin metabolites) and dinor-TxB2 (thromboxane metabolite) in five newly diagnosed type 1 diabetic patients during and after stopping cyclosporin therapy. In the resting state, cyclosporin had no effect on prostanoid excretion. In response to exercise, urinary excretion of 6-keto PGF1a was reduced by 50% (P less than 0.02), dinor-6-keto PGF1a by 15% (P less than 0.05) and dinor-TxB2 by 45% (P less than 0.02), while albumin excretion increased 4.5-fold (P less than 0.05) during cyclosporin therapy. Simultaneously, there was a rise in serum creatinine concentration, and renal biopsy specimens obtained from three patients showed periglomerular and interstitial fibrosis and tubular atrophy. After the discontinuation of cyclosporin therapy, serum creatinine concentrations returned to normal, histological changes improved and there was an associated rise in urinary prostanoid excretion. These data suggest that a reduction in renal prostanoid synthesis by cyclosporin may diminish renal blood flow and function, and lead to histological changes in the kidney.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Analysis of Variance; Blood Glucose; Cyclosporine; Diabetes Mellitus, Type 1; Exercise; Glycated Hemoglobin; Humans; Insulin; Kidney; Lactates; Male; Prostaglandins; Thromboxane A2

Topics: Blood Platelets; Diabetes Mellitus, Type 1; GTP-Binding Proteins; Humans; Platelet Activation; Polycythemia Vera; Receptors, Prostaglandin; Receptors, Thromboxane; Signal Transduction; Thromboxane A2

1. Human platelet thromboxane A2 receptor expression on the membrane surface is possibly dynamically regulated by changes either in the ligand concentration or in membrane fluidity. An increased thromboxane A2 production and a decreased membrane fluidity has been reported in diabetic patients. 2. In the present study the binding characteristics of platelet thromboxane A2 receptors have been investigated in nine diabetic patients (type I) and in 15 healthy control subjects by a radioligand-binding method using 9,11-dimethylmethane-11,12-methane-16-[3-125I-4-hydroxyphenyl]-13, 14- dihydro-13-aza-15-tetranor-thromboxane A2 as the radiolabelled ligand. 3. The maximum concentration of binding sites was 163 (SD 35) fmol/10(8) platelets (n = 15) with 987 (SD 209) receptors/platelet in controls, whereas in diabetic patients the maximum concentration of binding sites was 74.2 (SD 28) fmol/10(8) (n = 9) with 447 (SD 172) receptors/platelet (P less than 0.001). The dissociation constants were 18 (SD 4) nmol/l and 21 (SD 6) nmol/l (not significant) in control subjects and in diabetic patients, respectively. Glycated haemoglobin, which is reported to reduce membrane fluidity, was found to be negatively correlated (r = 0.60, P less than 0.05) with thromboxane A2 receptor number in the diabetic patient group. On the contrary, a positive linear correlation between the equilibrium dissociation constant and glycated haemoglobin was found in diabetic patients (r = 0.75, P less than 0.01).

Topics: Binding Sites; Blood Platelets; Cell Membrane; Diabetes Mellitus, Type 1; Female; Humans; Male; Middle Aged; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxanes

The follow-up of children and adolescents (n-41) suffering from insulin-dependent diabetes mellitus has demonstrated that the increase of the thromboxane/prostacyclin ratio pointing to the derangement of microcirculatory regulation occurs during the decompensation phase of the disease and is a risk factor of the development of diabetic complications. The revealed disorders of arachidonic acid metabolism may be one of the causes of the tendency towards decrease of pulse arterial pressure in grave diabetes mellitus.

Topics: Adolescent; Blood Pressure; Blood Vessels; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Epoprostenol; Humans; Infant; Microcirculation; Risk Factors; Thromboxane A2

Topics: Arachidonic Acid; Arachidonic Acids; Blood Platelets; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Platelet Activation; Thromboxane A2

We examined the effect of short- and long-term exercise on prostacyclin (prostaglandin I2 [PGI2]) and thromboxane A2 (TXA2) synthesis in type I (insulin-dependent) diabetic patients and healthy control subjects. PGI2 synthesis was assessed by determining the urinary excretion of 6-keto-PGF1 alpha and 2,3-dinor-6-keto-PGF1 alpha and TX synthesis by measuring TXB2 in serum and urine. In the resting state, prostanoid excretion and concentrations were similar in diabetic and control subjects. During 40 min of ergometric cycling exercise, the urinary excretion of 6-keto-PGF1 alpha (a hydration product of vasodilatory PGI2) increased 5.8-fold more in the 12 control subjects than in the 15 diabetic patients (P less than .02). Serum TXB2 concentration rose similarly in diabetic patients and control subjects (P less than .05). During a 75-km competitive cross-country ski race (7 h, 30 min), urinary excretion of 6-keto-PGF1 alpha rose 1.9-fold in 7 diabetic (P less than .05) and 3.3-fold in 10 control (P less than .001) subjects, whereas urinary dinor excretion, reflecting vascular PGI2 synthesis more closely, increased only in the control subjects (P less than .01). Urinary TXB2 excretion remained unchanged in both groups during long-term exercise. These data suggest that diabetic patients have normal PGI2 and TXA2 synthesis in the resting state but diminished PGI2 response to both acute and prolonged exercise.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Diabetes Mellitus, Type 1; Epoprostenol; Exercise; Humans; Physical Exertion; Reference Values; Thromboxane A2

Topics: Diabetes Mellitus, Type 1; Humans; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2

The effect of 24 hours and 7 days treatment with nisoldipine (10 mg, twice daily) on platelet function was studied in 12 normotensive volunteers of whom six were insulin-dependent diabetics without clinical evidence of vascular complications. Platelet aggregation was assessed by platelet rich plasma (PRP) and whole blood (WB) techniques. In addition, the effect of nisoldipine on platelet hyperaggregability following exercise was assessed. After taking nisoldipine for 24 hours, in vitro platelet hypersensitivity to adenosine diphosphate was observed in PRP (p less than 0.01) and WB (p less than 0.01), to adrenaline in WB (p less than 0.03), and to collagen in PRP (p less than 0.02). After seven days treatment, platelet sensitivities to all agonists at rest in both PRP and WB showed no differences from pre-treatment values. Exercise-induced platelet hypersensitivity in WB to all three agonists was unchanged after nisoldipine treatment. Plasma noradrenaline and adrenaline concentrations increased after 24 hours treatment, although changes in agonist EC50s at 24 hours were not related to changes in plasma catecholamine levels. No effects of nisoldipine were observed on platelet thromboxane B2 release in PRP, or on plasma beta-thromboglobulin levels. No differences in the effects of nisoldipine were observed between diabetic and non-diabetic subjects. Nisoldipine treatment for seven days is not associated with altered platelet function, but platelet hypersensitivity is observed after treatment for 24 hours in both insulin-dependent diabetics and controls.

Topics: Adenosine Diphosphate; beta-Thromboglobulin; Blood Platelets; Catecholamines; Collagen; Diabetes Mellitus, Type 1; Epinephrine; Humans; In Vitro Techniques; Nifedipine; Nisoldipine; Physical Exertion; Platelet Aggregation; Platelet Factor 4; Reference Values; Thromboxane A2

We have studied the functional importance of renal eicosanoids in renal hemodynamics of seven newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients by treatment with two structurally unrelated inhibitors of cyclooxygenase (i.e., piroxicam and sulindac). Glomerular filtration rate (GFR), renal plasma flow (RPF), daily urinary excretion of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, the stable hydrolysis product of prostacyclin), and thromboxane B2 (TXB2, the stable hydrolysis product of thromboxane A2) were measured before, during, and after piroxicam (all patients) or sulindac (3 patients) treatment. Urinary excretion of 6-keto-PGF1 alpha was significantly increased (P less than .01) in diabetic patients compared with seven healthy subjects, whereas urinary excretion of TXB2 was unchanged. The baseline value of GFR was significantly (P less than .01) higher in diabetic compared with normal volunteers, whereas baseline RPF was comparable in both groups. Piroxicam (20 mg/day) reduced urinary excretion of 6-keto-PGF1 alpha and TXB2 by 65.7 +/- 26 and 64.6 +/- 33%, respectively. These biochemical changes were temporally associated with the approximately 19% decrease in GFR (P less than .01). A week after discontinuation of the drug, GFR and urinary excretion of 6-keto-PGF1 alpha were still significantly (P less than .05) reduced, whereas urinary excretion of TXB2 returned to control values. In contrast, urinary excretion of eicosanoids and renal function were not affected by sulindac (0.4 g/day) treatment. No functional changes were detected in healthy subjects despite a similar suppression of renal cyclooxygenase activity when they were treated with piroxicam.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Creatinine; Diabetes Mellitus, Type 1; Female; Glomerular Filtration Rate; Humans; Kidney; Male; Piroxicam; Sulindac; Thromboxane A2

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

The time-dependent relationship between the levels of the reduced form of glutathione (GSH) and thromboxane A2 (TXA2) synthesis, as measured by the accumulation of TXB2, in platelets from human diabetic and control subjects was investigated during aggregation. In platelets from control subjects, the GSH level decreased to 21% of the initial level within 30 sec in response to arachidonic acid (1.65 mM) and rapidly recovered to 91% by 1 min. In platelets from diabetic subjects, the GSH level decreased to 3% of the initial level within 30 sec and recovered to only 41% by 1 min. During collagen (20 ug/ml) aggregation, platelets from control subjects had a 15 sec lag phase which was followed by a decrease in the GSH level to 21% of the initial level within 1 min and a recovery to 74% by 2 min. Platelets from diabetic subjects in response to collagen showed no lag phase and decreased to 10% of the initial level within 1 min which was followed by a recovery to 34% by 2 min. In all aggregations, the initial GSH level was significantly (p less than .001) lower in platelets from diabetic subjects and remained significantly (p less than .01) lower than GSH in platelets from control subjects throughout the aggregation. The amount of TXB2 formed by platelets from control subjects reached a maximum in response to arachidonic acid and collagen by 1 min and 2 min, respectively, whereas, the TXB2 continued to increase up to 4 min when platelets from diabetic subjects were aggregated. These data indicate that TXA2 synthesis occurs during the decrease in GSH and ceases when the GSH level recovers. The continued synthesis of TXA2 by platelets from diabetic subjects coincides with the gradual recovery of the GSH level.

Topics: Arachidonic Acids; Blood Platelets; Collagen; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glutathione; Humans; Male; Middle Aged; Platelet Aggregation; Thromboxane A2; Time Factors

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

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

Platelet vitamin E content and thromboxane A2 (TxA2) synthesis have been investigated in type I diabetic subjects and age- and sex-matched controls. Platelets, but not plasma, from diabetic subjects contained significantly lower vitamin E levels and synthesized significantly greater amounts of TxA2 when challenged with collagen or thrombin than platelets from control subjects. Conversion of exogenously added arachidonic acid to TxA2 was unaltered between platelets from control and diabetic groups. Platelet vitamin E content from control and diabetic groups combined exhibited a significant negative linear correlation with collagen- and thrombin-induced TxA2 production. These data suggest that low platelet vitamin E levels could be a contributing factor to the increased thromboxane synthesis demonstrated by platelets from the above type I diabetic subjects.

Topics: Adult; Animals; Blood Platelets; Collagen; Diabetes Mellitus, Type 1; Female; Humans; Male; Middle Aged; Rats; Thrombin; Thromboxane A2; Thromboxanes; Vitamin E

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

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