Inhibition of Platelet Function by Aspirin in Insulin Dependent Diabetics without Vascular Disease.

Abstract Abstract 4172 Diseases like diabetes that are associated with increased platelet production are reported to have decrease aspirin (ASA) induced platelet inhibition. ASA inhibition of platelet function is mediated via acetylation of platelet cylooxygenase, which is completed approximately 30 minutes after ingestion. Thereafter production of new non-acetylated platelets increases the proportion of normal platelets gradually reversing ASA platelet inhibition. We tested the hypothesis that insulin dependent diabetics (type 1) without clinical evidence of occlusive vascular disease have less aspirin platelet inhibition than normal controls. The amount of ASA (325mg) platelet inhibition was measured using the slope (S) of platelet prostaglandin agonist (PPA) stimulated light aggregation curve that decreases after ASA. Aggregation was measured at 3 time points: before ASA ingestion, time 0 (T0); 2 hours post ASA (T2); and 24 hours after ASA (T24). Percent recovery from aspirin inhibition was calculated using the formula (T24–T2)/ (T0-T2) x100. Eight adult insulin dependent diabetic patients without clinical evidence of vascular disease and who were not taking aspirin were compared with 11 nondiabetic controls. 24 hours after aspirin ingestion diabetic patients recovered 10% of their maximal ASA platelet inhibition compared to 13% in controls (p=0.69). We conclude that recovery of platelet function from ASA in insulin dependent diabetics without clinical vascular disease occurs at the same rate as normal controls, suggesting that the previously reported decrease in platelet inhibition in diabetic patients may be related to increased platelet production associated with clinically evident occlusive vascular disease. Disclosures: No relevant conflicts of interest to declare.

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Platelet function during continuous insulin infusion treatment in insulin-dependent diabetic patients

Diabetes ◽

10.2337/diabetes.34.11.1127 ◽

1985 ◽

Vol 34 (11) ◽

pp. 1127-1133 ◽

Cited By ~ 29

Author(s):

R. K. Mayfield ◽

P. V. Halushka ◽

H. J. Wohltmann ◽

M. Lopes-Virella ◽

J. K. Chambers ◽

...

Keyword(s):

Platelet Function ◽

Insulin Infusion ◽

Diabetic Patients ◽

Insulin Dependent ◽

Insulin Dependent Diabetic ◽

Continuous Insulin Infusion

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Effects of somatostatin on the behaviour of thromboxane B2 and β-thromboglobulin in type I diabetes

Acta Endocrinologica ◽

10.1530/acta.0.1090104 ◽

1985 ◽

Vol 109 (1) ◽

pp. 104-107 ◽

Cited By ~ 2

Author(s):

G. Gragnoli ◽

A. M. Signorini ◽

I. Tanganelli

Keyword(s):

Platelet Function ◽

Type I Diabetes ◽

Thromboxane B2 ◽

Diabetic Patients ◽

Base Line ◽

Type I ◽

Control Subjects ◽

Pharmacological Studies ◽

Insulin Dependent ◽

Insulin Dependent Diabetic

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

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Platelet Function in Uncomplicated Insulin-dependent Diabetic Patients at Rest and Following Exercise

Diabetic Medicine ◽

10.1111/j.1464-5491.1988.tb01031.x ◽

1988 ◽

Vol 5 (5) ◽

pp. 469-473 ◽

Cited By ~ 11

Author(s):

T. J. Hendra ◽

J. Oughton ◽

C. C. T. Smith ◽

D. J. Betteridge ◽

J. S. Yudkin

Keyword(s):

Platelet Function ◽

Diabetic Patients ◽

Insulin Dependent ◽

Insulin Dependent Diabetic

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Defects in Filamin A (FLNa) in Women with X-Linked Filaminopathies: Abnormalities in Platelet Production and Platelet Function

Blood ◽

10.1182/blood.v118.21.1152.1152 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1152-1152

Author(s):

Paquita Nurden ◽

Marijke Bryckaert ◽

Eliane Berrou ◽

Frédéric Adam ◽

Jean-Marie Daniel Lamazière ◽

...

Keyword(s):

Point Mutation ◽

Platelet Function ◽

Conflicts Of Interest ◽

Thrombus Formation ◽

Critical Role ◽

Signalling Pathway ◽

Comparative Genomic ◽

Giant Platelets ◽

Platelet Production ◽

Abnormal Distribution

Abstract Abstract 1152 Filamin (FLNa) is a major component of the platelet cytoskeleton. Platelet FLNa has a critical role in attaching the Von Willebrand Factor (VWF) receptor GPIb-IX-V and integrins to the actin cytoskeleton. Recently, in an animal model, FlnA has been shown to play an important role in platelet function involving ITAM-containing receptor signalling and also in platelet production. Filaminopathies linked to mutations in the X-linked FLNA gene are associated with a range of rare diseases such as periventricular nodular heterotopia (PVNH), otopalatidigital and cardiac valvular dystrophy. We have studied three women with FLNA mutations. For two of them (P1and P2) mutations were associated with PVNH, for the third patient (P3) only macrothrombocytopenia was detected. For patient P1 a heterozygous frameshift point mutation (c.4573_4insA, p.Tyr1525X) was present in exon 27 of FLNA. For patient 2, comparative genomic hybridization (array-CGH) revealed a heterozygous intragenic deletion involving FLNA exons 31–32 to 48. Patient P3 has a novel heterozygous point mutation c.5407G>A, p.Glu1803Lys affecting a glutamic acid residue that is highly conserved between species. Electron microscopy showed for all the patients a population of large platelets with a round shape and abnormal distribution of alpha-granules. In vitro culture of megakaryocytes (MKs) showed an abnormal and faster CD34+ platelet production compared to controls. Many MKs showed signs of abnormal fragmentation (confocal microscopy and EM) indicating an important role of FlnA in the early formation of proplatelets and in the localisation of granules. For patients P1 and P2 a minor population of platelets and also of MKs was found to be devoid of FLNa; for patient P3 with the missense mutation the localization of FLNa was heterogeneous with zones of individual MKs lacking FLNa. Western Blotting revealed a degraded form of FLNa in platelets that was particularly evident for P3 but residual intact FLNa always remained present in this X-linked syndrome. Platelet function testing in all patients showed an abnormal response to collagen and VWF. Thrombus formation under flow (300s−1) on collagen, was significantly decreased for the P1 and P3 but was partially restored for P1 at 1500s−1. The signalling pathway of GPVI, as shown by the phosphorylation of the tyrosine kinase Syk, was reduced. On a VWF matrix at 1500s−1, thrombus formation was identical between control and P1 and P2 but increased for P3. However, at higher shear rates (5000s−1), thrombus formation was drastically diminished for P1 while normal for P2 and remained increased for P3. In comparison with published animal studies where Flna is specifically deleted in the MK lineage (Jurak Begonja A, et al, Blood 2011 June 7, online) our results for women with different FLNA mutations suggest milder defects of the megakaryocytic-platelet lineage than in the mouse model and depending on the location of the mutation. For all patients we found giant platelets, and an abnormal distribution of FLNa. More variability was found for platelet function. These results resemble those obtained for the mice that linked the GPVI signalling pathway to FLNa. Nevertheless, with all the different mutations an altered platelet production led to the presence of giant platelets with an abnormal granule distribution. These results showing that platelet production was affected for all cases imply that platelet production is very dependant on FLNa concentration and integrity. Disclosures: No relevant conflicts of interest to declare.

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Fasting and postmeal phenylalanine metabolism in mild type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1992.263.5.e877 ◽

1992 ◽

Vol 263 (5) ◽

pp. E877-E883 ◽

Cited By ~ 4

Author(s):

G. Biolo ◽

P. Tessari ◽

S. Inchiostro ◽

D. Bruttomesso ◽

L. Sabadin ◽

...

Keyword(s):

Insulin Dependent Diabetes Mellitus ◽

Dependent Diabetes Mellitus ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Glucose Levels ◽

Isotope Technique ◽

Insulin Dependent ◽

Kinetics Of ◽

Normal Controls

We have investigated postabsorptive and postprandial phenylalanine kinetics in non-obese type 2 diabetic patients [non-insulin-dependent diabetes mellitus (NIDDM)], using a double-isotope technique and the constant oral administration of a synthetic mixed meal. Fasting and postmeal glucose levels were increased (P < 0.01) in NIDDM (165 +/- 16 to 226 +/- 24 mg/dl), with respect to normal controls (85 +/- 3 to 102 +/- 6 mg/dl). Fasting insulin concentrations were comparable in NIDDM (13 +/- 2 microU/ml) and in normals (12 +/- 2 microU/ml), but after the meal it increased less (P < 0.07) in NIDDM vs. normals (to 36 +/- 5 vs. 56 +/- 12 microU/ml, respectively; P < 0.01 vs. basal for both). Postabsorptive phenylalanine rate of appearance (R(a)) in NIDDM (0.63 +/- 0.08 mumol.kg-1 x min-1) was comparable to that of controls (0.73 +/- 0.05 mumol.kg-1 x min-1, not significant). During the meal, total and endogenous phenylalanine R(a), splanchnic uptake, oxidation, and nonoxidative disposal of the ingested phenylalanine were also comparable in the two groups. These data indicate that fasting and postprandial kinetics of the essential amino acid phenylalanine are normal in NIDDM.

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β-Thromboglobulin, Platelet Production Time and Platelet Function in Vascular Disease

British Journal of Haematology ◽

10.1111/j.1365-2141.1979.tb03727.x ◽

1979 ◽

Vol 43 (1) ◽

pp. 127-136 ◽

Cited By ~ 91

Author(s):

G. Cella ◽

J. Zahavi ◽

H. A. de Haas ◽

V. V. Kakkar

Keyword(s):

Vascular Disease ◽

Platelet Function ◽

Production Time ◽

Platelet Production

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Platelet Function During Continuous Insulin Infusion Treatment in Insulin-dependent Diabetic Patients

Diabetes ◽

10.2337/diab.34.11.1127 ◽

1985 ◽

Vol 34 (11) ◽

pp. 1127-1133 ◽

Cited By ~ 23

Author(s):

R. K. Mayfield ◽

P. V. Halushka ◽

H. J. Wohltmann ◽

M. Lopes-Virella ◽

J. K. Chambers ◽

...

Keyword(s):

Platelet Function ◽

Insulin Infusion ◽

Diabetic Patients ◽

Insulin Dependent ◽

Insulin Dependent Diabetic ◽

Continuous Insulin Infusion

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Simultaneous inhibition by pirenzepine of the GH responses to GnRH and TRH in insulin-dependent diabetics and in patients with major depression

Acta Endocrinologica ◽

10.1530/acta.0.1200143 ◽

1989 ◽

Vol 120 (2) ◽

pp. 143-148 ◽

Cited By ~ 4

Author(s):

V. Coiro ◽

R. Volpi ◽

L. Capretti ◽

G. Speroni ◽

A. Castelli ◽

...

Keyword(s):

Major Depression ◽

Previous Treatment ◽

Insulin Dependent Diabetes Mellitus ◽

Dependent Diabetes Mellitus ◽

Diabetic Patients ◽

Cholinergic Mechanism ◽

Insulin Dependent ◽

Muscarinic Cholinergic ◽

Male Patients ◽

Normal Controls

Abstract. The present study was undertaken in order to establish whether muscarinic cholinergic receptors are involved in the anomalous GH response to GnRH in men with insulin-dependent diabetes mellitus and in male patients with major depression. For this purpose, 16 male diabetics, 18 depressed men and 9 normal controls were tested with GnRH (25 μg iv) with and without previous treatment with the muscarinic cholinergic receptor blocker pirenzepine (40 mg iv 10 min before GnRH). Additional experiments with TRH (200 μg iv 10 min after pirenzepine) were performed in the same subjects and used for comparison between responders to TRH and GnRH. The administration of GnRH stimulated GH release in 12 out of the 16 diabetics and in 8 out of the 18 depressed patients, but not in the normal controls. Control and diabetic non-responders to GnRH did not respond to TRH. In contrast, all diabetic responders to GnRH, except 2, showed paradoxical GH responses to TRH. All depressed responders to GnRH and 3 of the non-responders, were responsive to TRH. The pattern and magnitude of the secretory responses to TRH and GnRH were similar in depressed and diabetic patients. When the effects of GnRH and TRH were restudied in the presence of pirenzepine, neither GnRH nor TRH enhanced the serum concentrations of GH in any patient. These data indicate that a muscarinic cholinergic mechanism is involved in the anomalous responses of GH to GnRH and TRH in diabetic men and in male patients affected by major depression.

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Regional Cerebral Glucose Transport in Insulin-Dependent Diabetic Patients Studied Using [11C]3-O-Methyl-D-Glucose and Positron Emission Tomography

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1986.37 ◽

1986 ◽

Vol 6 (2) ◽

pp. 240-244 ◽

Cited By ~ 46

Author(s):

D. J. Brooks ◽

J. S. R. Gibbs ◽

P. Sharp ◽

S. Herold ◽

D. R. Turton ◽

...

Keyword(s):

Positron Emission Tomography ◽

White Matter ◽

Plasma Glucose ◽

Emission Tomography ◽

Diabetic Patients ◽

Glucose Levels ◽

Positron Emission ◽

Insulin Dependent ◽

Insulin Dependent Diabetic ◽

Normal Controls

Regional cerebral [11C]3- O-methyl-d-glucose ([11C]MeG) uptake kinetics have been measured in five insulin-dependent diabetic patients and four normal controls using positron emission tomography (PET). Concomitant measurement of regional cerebral blood volume and CBF enabled corrections for the presence of intravascular [11C]MeG signal in cerebral regions of interest to be carried out, and regional cerebral [11C]MeG unidirectional extraction fractions to be computed. Four of the five diabetic subjects were studied with their fasting plasma glucose level clamped at a normoglycaemic level (4 m M), and four were studied at hyperglycaemic plasma glucose levels (mean 13 m M). The four diabetic subjects whose fasting plasma glucose levels were clamped at a normoglycaemic level of 4 m M had mean fasting whole-brain, cortical, and white matter [11C]MeG extraction fractions of 15, 15, and 16%, respectively, values similar to those found for the four normal controls (whole brain, 14%; cortex, 13%; white matter, 17%). Mean regional cerebral [11C]MeG extraction fractions were significantly reduced in diabetic subjects during hyperglycaemia whether their plasma insulin levels were undetectable or whether they were raised by continuous intravenous insulin infusion. Such a reduction in [11C]MeG extraction under hyperglycaemic conditions can be explained entirely in terms of increased competition between [11C]MeG and d-glucose for the passive facilitated transport carrier system for hexoses across the blood–brain barrier (BBB). It is concluded that the number and affinity of d-glucose carriers present in the BBB are within normal limits in treated insulin-dependent diabetic subjects. In addition, insulin appears to have no effect on the transport of d-glucose across the BBB.

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