Insulin Increases Guanosine-3′ ,5′-Cyclic Monophosphate in Human Platelets: A Mechanism Involved in the Insulin Anti-Aggregating Effect

Trovati, Mariella; Massucco, Paola; Mattiello, Luigi; Mularoni, E.; Cavalot, Franco; Anfossi, Giovanni

doi:10.2337/diab.43.8.1015

Cited by 43 publications

(26 citation statements)

References 24 publications

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“…In addition, insulin suppresses ROS generation and the expression of p47 phox , a key component of NADPH oxidase, the enzyme that generates the superoxide radical, consistent with the potent antioxidant effect of insulin (4,9). Two other important effects of insulin include vasodilatation and the inhibition of platelet aggregation (10)(11)(12). These effects are mediated by an increase in NO release and NO synthase activity in the endothelium and the platelet (13,14).…”

Section: Mechanism Of Insulin Actionmentioning

confidence: 80%

Insulin infusion in acute illness

Dandona

Mohanty²,

Chaudhuri³

et al. 2005

Journal of Clinical Investigation

129

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Section: Mechanism Of Insulin Actionmentioning

confidence: 80%

Insulin infusion in acute illness

Dandona

Mohanty²,

Chaudhuri³

et al. 2005

Journal of Clinical Investigation

129

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“…In addition to this vasoactive action in the peripheral vasculature, insulin directly affects myocardial perfusion by enhancing hyperemic myocardial blood flow in a dose-dependent manner (20). Insulin also has other positive effects, most notably the capability to inhibit platelet aggregation by increasing cGMP (21) and an anti-inflammatory and profibrinolytic effect at least in patients with acute myocardial infarction (22). Postprandial glucose peak (4,23,24) is an independent risk factor, especially with respect to CVD.…”

Section: Figure 1-mean ϯ Se Of Plasma Glucose (Left Upper Panel) Plamentioning

confidence: 99%

Effects of Different Insulin Regimes on Postprandial Myocardial Perfusion Defects in Type 2 Diabetic Patients

et al. 2006

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OBJECTIVE -Postprandial glycemia is an independent risk factor for cardiovascular disease that is more powerful than fasting glycemia and determines myocardial perfusion defects in type 2 diabetes. We examined the efficacy of two different insulin regimes (regular insulin and insulin analog) in controlling postprandial hyperglycemia and in preventing myocardial perfusion abnormalities. RESEARCH DESIGN AND METHODS-A total of 20 consecutive type 2 diabetic patients and 20 control subjects were enrolled in this randomized, three-way, cross-over, placebocontrolled study. Myocardial perfusion was assessed by myocardial contrast echocardiography (MCE) in fasting and postprandial (120 min) state.RESULTS -Insulin analog was associated with lower, but not statistically significant, postprandial glycemia than regular insulin (glucose increase: 116 Ϯ 8 vs. 136 Ϯ 5%, P ϭ NS). However, the area under the curve following insulin analog was significantly lower than regular insulin (18,354 Ϯ 702 vs. 20,757 Ϯ 738 mg per 120 min, P ϭ 0.032). D iabetes is associated with a markedly increased risk of cardiovascular disease (CVD), and this excess risk is not explained by the increase of conventional cardiovascular risk factors (1). Several studies confirmed that tight glycemic control reduces and delays late diabetes and microvascular complications (2,3). Considerable data indicate that postprandial plasma glucose level might be an independent risk factor of CVD that is more powerful than fasting hyperglycemia, and the presence of postprandial hyperglycemia is a significant predictor of myocardial infarction and death (4). Recently, the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study confirmed that postload hyperglycemia increases mortality and that postload glucose is a better predictor of mortality than fasting glucose (5). Postprandial hyperglycemia could result in labile nonenzymatic glycation, promotion of thrombosis, and production of free radicals that could generate tissue damage and favor the development of micro-and macrovascular complications (6). In a recent study including type 2 diabetic patients, postprandial hyperglycemia determined myocardial perfusion defects secondary to deterioration in microvascular function (7). Thus, clinically it seems reasonable to avoid excessive postprandial hyperglycemia in the management of diabetes (8).The present study was conducted to compare the efficacy of two different insulin regimes (regular insulin or insulin analog) in controlling postprandial hyperglycemia and preventing myocardial perfusion defects in type 2 diabetic patients.RESEARCH DESIGN AND METHODS -Among type 2 diabetic patients regularly attending the Diabetes Clinic of University of Padua, we enrolled 20 consecutive patients with a diagnosis of type 2 diabetes for Ն6 months but Յ10 years, aged Յ60 years, with a BMI of 26.4 Ϯ 1.4 and HbA 1c (A1C) of 7.2 Ϯ 1%. All patients were managed by dietary therapy. Exclusion criteria included any hepatic disease, renal disease (plasma...

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“…When platelets were preincubated with the general phosphodiesterase inhibitor, IBMX (1 mM) (18), basal cAMP levels were increased 2-fold (14.8 Ϯ 3.0 versus 7.4 Ϯ 1.1 pmol/10 9 platelets) as a consequence of inhibition of platelet cAMP phosphodiesterase. However, addition of apoE⅐DMPC vesicles to the system did not invoke a further rise in cAMP (14.7 Ϯ 3.4 versus 14.8 Ϯ 3.0 pmol/10 9 platelets at 50 g of protein/ml of apoE⅐DMPC; Fig.…”

Section: Inhibition Of Platelet Aggregation By Apoe⅐dmpc-aqueousmentioning

confidence: 99%

Apolipoprotein E Inhibits Platelet Aggregation through the L-Arginine:Nitric Oxide Pathway

Riddell

Graham

Owen

1997

Journal of Biological Chemistry

183

143

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We have previously reported that plasma apolipoprotein (apo) E-containing high density lipoprotein particles have a potent anti-platelet action, apparently by occupying saturable binding sites in the cell surface. Here we show that purified apoE (10 -50 g/ml), complexed with phospholipid vesicles (dimyristoylphosphatidylcholine, DMPC), suppresses platelet aggregation induced by ADP, epinephrine, or collagen. This effect was not due to sequestration of cholesterol from platelet membranes; apoE⅐DMPC chemically modified with cyclohexanedione (cyclohexanedione-apoE⅐DMPC) did not inhibit aggregation but nevertheless removed similar amounts of cholesterol as untreated complexes, about 2% during the aggregation period. Rather we found that apoE influenced intracellular platelet signaling. Thus, apoE⅐DMPC markedly increased cGMP in ADP-stimulated platelets which correlated with the resulting inhibition of aggregation (r ‫؍‬ 0.85; p < 0.01, n ‫؍‬ 10), whereas cyclohexanedione-apoE⅐DMPC vesicles had no effect. One important cellular mechanism for up-regulation of cGMP is through stimulation of nitric oxide (NO) synthase, the NO generated by conversion of Larginine to L-citrulline, binds to and activates guanylate cyclase. This signal transduction pathway was implicated by the finding that NO synthase inhibitors of distinct structural and functional types all reversed the anti-platelet action of apoE, whereas a selective inhibitor of soluble guanylate cyclase, 1H- platelets) than controls (0.18 ؎ 0.03; p < 0.05). In addition, hemoglobin which avidly binds NO also suppressed the anti-aggregatory effect, indicating that apoE stimulated sufficient production of NO by platelets for extracellular release to occur. We conclude that apoE inhibits platelet aggregation through the L-arginine:NO signal transduction pathway. Human apolipoprotein E (apoE)1 is a 299-residue protein of molecular mass 34 kDa found in the surface of circulating triglyceride-rich lipoproteins (very low density lipoprotein and chylomicrons, or their remnants) and certain HDL particles (1). Its major function is to mediate hepatic clearance of lipoproteins through interaction with two receptors, the low density lipoprotein or B,E receptor and an apoE-specific receptor, most probably the low density lipoprotein receptor-related protein (2). When the apoE polypeptide is dysfunctional or absent severe hyperlipidemia and atherosclerosis in humans or animal models ensues (1, 3-5). Although apoE is synthesized predominantly by the liver, macrophages also secrete apoE; this appears important for facilitating local cholesterol redistribution, for reverse cholesterol transport, and for restricting development of atherosclerotic lesions (6). Indeed, atherosclerosis in apoE-deficient (apoE Ϫ/Ϫ ) mice can be prevented by transplantation of normal murine bone marrow cells (5), by macrophage-specific expression of the human apoE transgene (7), or by adenovirus-mediated gene replacement (8).Recently, we proposed an additional anti-atherogenic role for apoE. We found that H...

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Insulin Increases Guanosine-3′ ,5′-Cyclic Monophosphate in Human Platelets: A Mechanism Involved in the Insulin Anti-Aggregating Effect

Cited by 43 publications

References 24 publications

Insulin infusion in acute illness

Insulin infusion in acute illness

Effects of Different Insulin Regimes on Postprandial Myocardial Perfusion Defects in Type 2 Diabetic Patients

Apolipoprotein E Inhibits Platelet Aggregation through the L-Arginine:Nitric Oxide Pathway

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