Platelet resistance to nitrates in obesity and obese NIDDM, and normal platelet sensitivity to both insulin and nitrates in lean NIDDM (original) (raw)
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Altered platelet functions in non-insulin-dependent diabetes mellitus (NIDDM)
Thrombosis Research, 1994
We have studied platelet aggregation and membrane fluidity, along with various biochemical parameters, in 19 non-insulin-dependent diabetes mellitus (NIDDM) patients prior to control of blood sugar, 11 patients after control of blood sugar, and 26 normal subjects. Platelet cholestrol: phospholipid ratio and basal levels of ) [Ca+]were comparable between normal and uncontrolled NIDDM. Basal levels of malonaldehyde (MDA) and the levels of [Ca++], as well as MDA after the addition of arachidonic acid, were 2.5-fold, 5-fold, and 2.5-fold higher, respectively, in the uncontrolled NIDDM group than normals. Platelet aggregation in response to ADP (0.25 uM), epinephrine (1.25 uM), and arachidonic acid (0.25 mM) was significantly higher in uncontrolled NIDDM than in normals (75%, 40% and 52%, respectively). Platelet fluorescence polarization was also higher in NIDDM patients indicating decreased membrane fluidity in such patients as compared to normals. After control of blood sugar in 11 NIDDM patients, agonist-stimulated platelet aggregation and other biochemical parameters were comparable to normals.
Thrombosis Research, 1996
In this study, we investigated the effects of a 3-min insulin incubation both at physiological and at supraphysiological concentrations on platelet aggregation and intraplatelet cyclic guanosine monophosphate (cGMP) levels both in the absence and in the presence of phosphodiesterase inhibition. We observed that insulin at concentrations in the range 0.252 nmol/L decreases platelet response to adenosine 5diphosphate (ADP), being Effective Dose 50 (ED,,) for ADP with 2 nmol/L insulin 164+_15 % of the basal value, p=O.O05; furthermore, insulin increases intraplatelet content of cGMP (from basal 7.320.6 pmol/lOg plts to 14.6-1.2 pmol/lOY plts with 2 nmol/L insulin, p=O.OOOl) and does not affect the platelet cGMP increase induced by nitrates. On the contrary, at very elevated concentrations (25-200 nmol/L) insulin increases platelet aggregation to ADP (ADP El&, with 200 nmol/L insulin being 81~4% of the basal value, p=O.Ol), decreases intraplateletcontent of cGMP (from basal 7.2~0.1 pmol/l@ plts to 5.7~0.2 pmol/lOg plts with 200 nmol/L insulin, p=O.Ol) and attenuates the platelet cGMP increase induced by nitrates. When cGMP catabolism is inhibited by theophylline or the selective cGMP phosphodiesterase inhibitor zaprinast, insulin shows anti-aggregating effects also at highly supraphysiological concentrations (25-200 nmol/L). These results indicate that insulin, depending on the concentrations employed, shows opposite effects on platelet function, and they provide information about the mechanisms involved: actually, insulin is able to increase both cGMP synthesis, through guanylate cyclase activation, and cGMP catabolism, through phosphodiesterase activation. At physiological or slightly supraphysiological concentrations the first phenomenon is prevailing, so that cGMP intraplatelet values increase and insulin shows antiaggregating properties, whereas, at supraphysiological concentrations, insulin reduces cGMP levels through a prevailing phosphodiesterase activation, as supported by the fact that, when cGMP catabolism is prevented, insulin shows anti-aggregating properties also at the highest concentrations used.
Insulin Resistance as a Determinant of Platelet Activation in Obese Women
Journal of the American College of Cardiology, 2006
OBJECTIVES We tested the hypothesis that insulin resistance, per se, contributes to increased platelet activation in obesity, independently of underlying inflammation. BACKGROUND 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. METHODS 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. RESULTS Obese women had significantly (p Ͻ 0.0001) higher 11-dehydro-thromboxane B 2 (11dehydro-TXB 2) 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 Ϫ1 /[U/ml], p Ͻ 0.002) and adiponectin (6.3 vs. 10 g/ml, p Ͻ 0.01) than control subjects. On multiple regression analysis, waist-to-hip ratio ( ϭ 0.27, p Ͻ 0.05) and S I ( ϭ Ϫ0.72, p Ͻ 0.04) predicted 11-dehydro-TXB 2 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-TXB 2 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 (ϩ92%) and decreased CD40L (Ϫ27%), CRP (Ϫ37%), and 11-dehydro-TXB 2 (Ϫ53%) (p Ͻ 0.05). Consistently, improvement of insulin sensitivity achieved with pioglitazone significantly decreased urinary 11-dehydro-TXB 2 excretion (Ϫ43%, p Ͻ 0.05) without changes in body weight. CONCLUSIONS Insulin resistance is a major determinant of platelet activation in female obesity.
Journal of Cardiology, 2010
Background and purpose: Mean platelet volume (MPV), an indicator of platelet activation, has been shown to be elevated in patients with coronary artery disease (CAD) in some studies. Insulin resistance contributes to increased platelet activation and it is one of the risk factors for CAD. The aim of this study was to assess the relationship between insulin resistance and MPV in non-obese, non-diabetic patients with CAD. Methods and subjects: Seventy-seven non-obese, non-diabetic CAD patients were divided into two groups, insulin resistant and insulin sensitive according to the homeostasis model assessment insulin resistance index (HOMA-IR). The insulin-resistant group was composed of 45 patients (30 males/15 females; mean age 59.8 ± 11.1 years). The insulin-sensitive group was composed of 32 patients (17 males/15 females; mean age 58.9 ± 12.2 years). Results: Insulin and HOMA-IR values were significantly higher in insulin-resistant CAD patients than in insulin-sensitive CAD patients. The MPV values were significantly higher in insulinresistant CAD patients than in insulin-sensitive CAD patients (8.6 ± 1.0 fl vs. 8.0 ± 0.7 fl; respectively, p = 0.01). The MPV was poorly correlated with HOMA-IR (r = 0.30, p = 0.054) and insulin (r = 0.22, p = 0.053). Conclusions: We have shown that MPV was significantly elevated in insulin-resistant non-obese, non-diabetic CAD patients when compared to insulin-sensitive non-obese, non-diabetic CAD patients.
Decreased nitric oxide synthase activity in platelets from IDDM and NIDDM patients
Diabetologia, 1998
Nitric oxide (NO) has been shown to inhibit platelet activation through an increase in cytoplasmic cGMP levels . Recent evidence suggests that the cGMP increase induced by insulin in human platelets, which accounts for the antiaggregatory effect of the hormone, is mediated by . NO production within the platelet is made possible by the presence of a constitutive isoform of the enzyme nitric oxide synthase (NOS) , which has been recently isolated from human platelets . Platelet NOS has a distinct molecular weight (150 kDa) and its amino acid sequence has been deduced from its mRNA sequence .
Diabetes Care, 2010
OBJECTIVE Acute, short-term hyperglycemia enhances high shear stress–induced platelet activation in type 2 diabetes. Several observations suggest that platelets in type 2 diabetes are resistant to inhibition by aspirin. Our aim was to assess comparatively the effect of aspirin, a nitric oxide–donating agent (NCX 4016), their combination, or placebo on platelet activation induced by acute hyperglycemia in type 2 diabetes. RESEARCH DESIGN AND METHODS In a double-blind, placebo-controlled, randomized trial, 40 type 2 diabetic patients were allocated to 100 mg aspirin once daily, 800 mg NCX 4016 b.i.d., both of them, or placebo for 15 days. On day 15, 1 h after the morning dose, a 4-h hyperglycemic clamp (plasma glucose 13.9 mmol/l) was performed, and blood samples were collected before and immediately after it for platelet activation and cyclooxygenase-1 (COX-1) inhibition studies. RESULTS Acute hyperglycemia enhanced shear stress–induced platelet activation in placebo-treated patients...
Experimental and Clinical Endocrinology & Diabetes, 2017
Macro- and microvascular complications are currently the principal causes of morbidity and mortality in patients with diabetes mellitus. Aim of this study was to determine if type 2 diabetic patients with nephropathy and coronary artery disease showed altered platelet-derived nitric oxide (NO) production, compared with diabetic subjects without complications, and if this alteration is also present in their diabetic offspring. In this case-control observational study, platelet NO and peroxynitrite content was determined on plasma from 60 male adult type 2 diabetic patients and 60 male offspring type 2 diabetic patients. Plasmatic levels of homocysteine were also determined in the same individuals. Moreover, Western blot analysis of platelet lysates was performed with specific monoclonal antibody for endothelial (eNOS) and inducible (iNOS) nitric oxide synthase. Our study showed a lower piastrinic production of NO in the group of parents without complications (ADH), compared with the ...