Platelet Resistance to Nitrates in Obesity and Obese NIDDM, and Normal Platelet Sensitivity to Both Insulin and Nitrates in Lean NIDDM

Anfossi, Giovanni; Mularoni, E.; Burzacca, S.; Ponziani, Maria Chantal; Massucco, Paola; Mattiello, Luigi; Cavalot, Franco; Trovati, Mariella

doi:10.2337/diacare.21.1.121

Cited by 105 publications

(79 citation statements)

References 29 publications

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“…41,42 IRSindependent pathways are also involved in platelet hyperreactivity caused by insulin resistance such as impairment in platelet sensitivity to nitric oxide (NO) and prostacyclin. 43,44 Both mediators are released by the endothelium and retard platelet activation. Therefore, impaired response to NO and prostacyclin is associated with enhanced platelet reactivity.…”

Section: Insulin Deficiency and Resistancementioning

confidence: 99%

Diabetes and Antiplatelet Therapy in Acute Coronary Syndrome

2011

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Section: Insulin Deficiency and Resistancementioning

confidence: 99%

Diabetes and Antiplatelet Therapy in Acute Coronary Syndrome

2011

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“…Blood platelet counts were similar in the nonobese and obese subjects and were not altered by hyperinsulinemia (189Ϯ9ϫ10 9 and 182Ϯ10ϫ10 9 per liter in the nonobese and obese subjects, respectively, at baseline; 178Ϯ10ϫ10 9 and 180Ϯ8ϫ10 9 per liter in the nonobese and obese subjects, respectively, at the end of the insulin infusion). In the nonobese subjects, platelet deposition to collagen in wholeblood perfusion decreased from 4.3Ϯ0.6ϫ10 6 per square centimeter before to 3.5Ϯ0.4ϫ10 6 per square centimeter at the end of hyperinsulinemia (PϽ0.05 versus basal values, Figure 1).…”

Section: Effect Of In Vivo Insulin On Platelet-collagen Interaction Amentioning

confidence: 83%

“…26 This protective effect correlates with insulin-induced increases of circulating NO concentrations. Platelets from insulin-resistant obese 9 and hypertensive 27 subjects are also resistant to platelet-inhibitory effects of nitrates/NO. Also, NO fails to inhibit platelet aggregation to the same extent in patients with stable angina or acute coronary syndromes compared with nonischemic patients.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Platelet-Collagen Interaction

Westerbacka

Yki‐Järvinen

Turpeinen

et al. 2002

ATVB

119

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Abstract-Insulin resistance is associated with an increased risk of atherothrombotic vascular disease, but the mechanisms are poorly understood. We determined how insulin in vivo regulates platelet activation in nonobese and obese subjects by using methods mimicking thrombus formation. Twelve nonobese (aged 42Ϯ2 years, body mass index 24.0Ϯ0.4 kg/m 2 ) and 14 obese (aged 43Ϯ1 years, body mass index 37.2Ϯ1.5 kg/m 2 ) subjects were studied under euglycemic hyperinsulinemic (3-hour insulin infusion of 1 mU · kg Ϫ1 · min Ϫ1) conditions. Before and at the end of hyperinsulinemia, the following were determined: (1) platelet-related early hemostasis (shear rate of Ϸ4000 s Ϫ1) by platelet function analysis; (2) platelet deposition to collagen during whole-blood perfusion (shear rate of 1600 s Ϫ1 ); (3) aggregation responses to collagen, thrombin receptor-activating peptide, ADP, and epinephrine; and (4) platelet cGMP concentrations. Insulin action on glucose metabolism was 69% lower in the obese subjects (1.6Ϯ0.2 mg · kg Ϫ1 · min Ϫ1) than in the nonobese subjects (5.4Ϯ0.4 mg · kg Ϫ1 · min Ϫ1, PϽ0.0001). The in vivo insulin infusion inhibited platelet deposition to collagen from 4.3Ϯ0.6ϫ10 6 to 3.5Ϯ0.4ϫ10 6 per square centimeter in the nonobese subjects (PϽ0.05) but failed to do so in the obese subjects (5.2Ϯ0.8ϫ10 6 versus 5.5Ϯ0.7ϫ10 6 per square centimeter, PϭNS; PϽ0.01 versus nonobese subjects). Epinephrine-and ADP-primed closure times by platelet function analysis were prolonged by insulin in the nonobese but not the obese subjects (PϽ0.05 for between-group difference). In the nonobese subjects, insulin decreased aggregation to all agonists and significantly increased platelet cGMP concentrations (2.5Ϯ0.3 versus 3.2Ϯ0.5 pmol/10 9 for before versus after insulin, respectively; PϽ0.01). In the obese subjects, insulin did not alter collagen-induced aggregation or cGMP concentrations (1.9Ϯ0.2 versus 1.8Ϯ0.1 pmol/10 9 for before versus the end of in vivo hyperinsulinemia, respectively; PϭNS). These data demonstrate that normal in vivo insulin action inhibits platelet interaction with collagen under conditions mimicking thrombus formation and reduces aggregation to several agonists. These platelet-inhibitory actions of insulin are blunted or absent in obese subjects and could provide 1 mechanism linking insulin resistance to atherothrombotic disease. Key Words: insulin Ⅲ collagen Ⅲ nitric oxide Ⅲ obesity Ⅲ cGMP I nsulin resistance predisposes individuals to atherothrombotic vascular disease, but the mechanisms are incompletely understood. Human platelets have insulin receptors that participate in the regulation of platelet functions. 1 In vitro and in vivo studies have demonstrated that insulin inhibits platelet aggregation in healthy nonobese subjects. [2][3][4] In obese 2 and hypertensive 5 subjects, this antiaggregating effect of in vitro insulin has been shown to be blunted. These data suggest that insulin resistance also involves platelets, but it is currently unknown whether the resistance of platelets to insulin occ...

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“…[7][8][9][10] A poor hemodynamic response to organic nitrates has been observed in patients with congestive heart failure, 11,12 and this phenomenon has been termed nitrate resistance. Nitrate resistance has also been observed in platelets from patients with hypertension, 13 obese diabetes, 14 and stable angina pectoris. 15 However, the mechanism of nitrate resistance is still unknown.…”

mentioning

confidence: 82%

Long-Term Smoking Causes Nitroglycerin Resistance in Platelets by Depletion of Intraplatelet Glutathione

Haramaki

Ikeda

Takajo

et al. 2001

ATVB

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Abstract-We investigated whether platelet responsiveness to nitroglycerin (NTG) is maintained in long-term smokers and if not, the mechanism. In the absence or presence of NTG, intraplatelet reduced glutathione (GSH) levels and ADP-induced platelet aggregation and intraplatelet cGMP levels were measured in 10 long-term smokers and 10 age-matched nonsmokers. The intraplatelet GSH level was significantly lower in smokers than in nonsmokers (PϽ0.05).Platelet aggregation was dose-dependently inhibited by NTG in both groups; however, inhibition was significantly weaker in smokers. N-acetylcysteine (1 mmol/L), an exogenous thiol agent, significantly potentiated NTG-induced platelet inhibition in nonsmokers but not in smokers. The ADP-induced intraplatelet cGMP level was significantly greater in the presence of NTG in nonsmokers but not so in smokers. Because the effects of long-term smoking are multifactorial, a rabbit model was made by chronic administration of buthionine sulfoximine (BSO, nϭ6) to decrease intraplatelet GSH. The intraplatelet GSH level was significantly lower in BSO-treated rabbits than in saline-treated rabbits (PϽ0.001). The NTG-induced inhibition of platelet aggregation was significantly weaker in BSO rabbits. N-acetylcysteine-induced potentiation was not observed in BSO rabbits, whereas significant potentiation was found in saline rabbits. These findings were similar to those of long-term smokers. In contrast, the intraplatelet GSH-to-oxidized glutathione ratio, which represents the redox state of glutathione, was significantly lower in smokers than in nonsmokers, whereas no difference was found between saline rabbits and BSO rabbits. In conclusion, long-term smoking causes NTG resistance to aggregation in platelets, possibly through the depletion of intraplatelet GSH.

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Platelet Resistance to Nitrates in Obesity and Obese NIDDM, and Normal Platelet Sensitivity to Both Insulin and Nitrates in Lean NIDDM

Cited by 105 publications

References 29 publications

Diabetes and Antiplatelet Therapy in Acute Coronary Syndrome

Diabetes and Antiplatelet Therapy in Acute Coronary Syndrome

Inhibition of Platelet-Collagen Interaction

Long-Term Smoking Causes Nitroglycerin Resistance in Platelets by Depletion of Intraplatelet Glutathione

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