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Hyperglycemia-induced platelet activation in type 2 diabetes is resistant to aspirin but not to a nitric oxide-donating agent.

Gresele P, Marzotti S, Guglielmini G, Momi S, Giannini S, Minuz P, Lucidi P, Bolli GB - Diabetes Care (2010)

Bottom Line: 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.Pretreatment with aspirin, despite full inhibition of platelet COX-1, did not prevent it (-12.7 +/- 6.9 s, NS vs. placebo).On the contrary, pretreatment with the NO donor NCX 4016, alone or in combination with aspirin, suppressed platelet activation induced by acute hyperglycemia (NCX 4016 +10.5 +/- 8.3 s; NCX 4016 plus aspirin: +12.0 +/- 10.7 s, P < 0.05 vs. placebo for both).

View Article: PubMed Central - PubMed

Affiliation: Section of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Perugia, Italy. grespa@unipg.it

ABSTRACT

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 (basal closure time 63 +/- 7.1 s, after hyperglycemia 49.5 +/- 1.4 s, -13.5 +/- 6.3 s, P < 0.048). Pretreatment with aspirin, despite full inhibition of platelet COX-1, did not prevent it (-12.7 +/- 6.9 s, NS vs. placebo). On the contrary, pretreatment with the NO donor NCX 4016, alone or in combination with aspirin, suppressed platelet activation induced by acute hyperglycemia (NCX 4016 +10.5 +/- 8.3 s; NCX 4016 plus aspirin: +12.0 +/- 10.7 s, P < 0.05 vs. placebo for both). Other parameters of shear stress-dependent platelet activation were also more inhibited by NCX 4016 than by aspirin, despite lesser inhibition of COX-1.

Conclusions: Acute hyperglycemia-induced enhancement of platelet activation is resistant to aspirin; a NO-donating agent suppresses it. Therapeutic approaches aiming at a wider platelet inhibitory action than that exerted by aspirin may prove useful in patients with type 2 diabetes.

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A: Plasma glucose concentrations before and during the 4-h hyperglycemic clamp in the four treatment groups. No differences between groups were observed at any of the observation times. B and C: Shear stress–induced platelet activation using the O'Brien filtration test. Data are expressed as differences (Δ) between the values observed after the 4-h hyperglycemic clamp (post) and the values observed before (pre). B: Filter closure time expressed in seconds. C: Platelets retained between 20 and 40 s, expressed as a percentage of the platelet count before filtration. In the insets are reported results cumulating the two groups receiving NCX 4016 (w NCX) and the two groups not receiving it (w/o NCX). Data are expressed as means ± SEM. *P < 0.05 vs. placebo; §P < 0.05 vs. aspirin (ASA); #P < 0.05 vs. w/o NCX 4016. D: Platelet deposition on a collagen-coated surface under high shear rate (3,000 s−1). Data are expressed as differences (Δ) between the values observed after the 4-h hyperglycemic clamp (post) and the values observed before (pre). *P < 0.001 versus placebo.
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Figure 1: A: Plasma glucose concentrations before and during the 4-h hyperglycemic clamp in the four treatment groups. No differences between groups were observed at any of the observation times. B and C: Shear stress–induced platelet activation using the O'Brien filtration test. Data are expressed as differences (Δ) between the values observed after the 4-h hyperglycemic clamp (post) and the values observed before (pre). B: Filter closure time expressed in seconds. C: Platelets retained between 20 and 40 s, expressed as a percentage of the platelet count before filtration. In the insets are reported results cumulating the two groups receiving NCX 4016 (w NCX) and the two groups not receiving it (w/o NCX). Data are expressed as means ± SEM. *P < 0.05 vs. placebo; §P < 0.05 vs. aspirin (ASA); #P < 0.05 vs. w/o NCX 4016. D: Platelet deposition on a collagen-coated surface under high shear rate (3,000 s−1). Data are expressed as differences (Δ) between the values observed after the 4-h hyperglycemic clamp (post) and the values observed before (pre). *P < 0.001 versus placebo.

Mentions: The demographic data of the patients enrolled in the study are reported in Table 1. No significant differences in any of the demographic parameters were evident between the treatment groups. Fasting plasma glucose and insulin concentrations before the clamp were not different in the four study groups. After the beginning of glucose infusion, plasma glucose reached the target of 250 mg/dl by 31.6 ± 2.2 min, with no differences between groups (Fig. 1A). Plasma insulin increased in response to hyperglycemia (baseline = 12.1 ± 0.8 μU/ml and steady-state = 28.0 ± 4.2 μU/ml) with no significant differences between the groups, although with a trend to higher insulin levels upon hyperglycemia in the NCX 4016–treated groups. Platelet count was similar before the clamp in the four study groups and decreased slightly, but not significantly, after the clamp. Hematocrit values were similar at baseline in all study groups and remained unchanged after the clamp.


Hyperglycemia-induced platelet activation in type 2 diabetes is resistant to aspirin but not to a nitric oxide-donating agent.

Gresele P, Marzotti S, Guglielmini G, Momi S, Giannini S, Minuz P, Lucidi P, Bolli GB - Diabetes Care (2010)

A: Plasma glucose concentrations before and during the 4-h hyperglycemic clamp in the four treatment groups. No differences between groups were observed at any of the observation times. B and C: Shear stress–induced platelet activation using the O'Brien filtration test. Data are expressed as differences (Δ) between the values observed after the 4-h hyperglycemic clamp (post) and the values observed before (pre). B: Filter closure time expressed in seconds. C: Platelets retained between 20 and 40 s, expressed as a percentage of the platelet count before filtration. In the insets are reported results cumulating the two groups receiving NCX 4016 (w NCX) and the two groups not receiving it (w/o NCX). Data are expressed as means ± SEM. *P < 0.05 vs. placebo; §P < 0.05 vs. aspirin (ASA); #P < 0.05 vs. w/o NCX 4016. D: Platelet deposition on a collagen-coated surface under high shear rate (3,000 s−1). Data are expressed as differences (Δ) between the values observed after the 4-h hyperglycemic clamp (post) and the values observed before (pre). *P < 0.001 versus placebo.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2875435&req=5

Figure 1: A: Plasma glucose concentrations before and during the 4-h hyperglycemic clamp in the four treatment groups. No differences between groups were observed at any of the observation times. B and C: Shear stress–induced platelet activation using the O'Brien filtration test. Data are expressed as differences (Δ) between the values observed after the 4-h hyperglycemic clamp (post) and the values observed before (pre). B: Filter closure time expressed in seconds. C: Platelets retained between 20 and 40 s, expressed as a percentage of the platelet count before filtration. In the insets are reported results cumulating the two groups receiving NCX 4016 (w NCX) and the two groups not receiving it (w/o NCX). Data are expressed as means ± SEM. *P < 0.05 vs. placebo; §P < 0.05 vs. aspirin (ASA); #P < 0.05 vs. w/o NCX 4016. D: Platelet deposition on a collagen-coated surface under high shear rate (3,000 s−1). Data are expressed as differences (Δ) between the values observed after the 4-h hyperglycemic clamp (post) and the values observed before (pre). *P < 0.001 versus placebo.
Mentions: The demographic data of the patients enrolled in the study are reported in Table 1. No significant differences in any of the demographic parameters were evident between the treatment groups. Fasting plasma glucose and insulin concentrations before the clamp were not different in the four study groups. After the beginning of glucose infusion, plasma glucose reached the target of 250 mg/dl by 31.6 ± 2.2 min, with no differences between groups (Fig. 1A). Plasma insulin increased in response to hyperglycemia (baseline = 12.1 ± 0.8 μU/ml and steady-state = 28.0 ± 4.2 μU/ml) with no significant differences between the groups, although with a trend to higher insulin levels upon hyperglycemia in the NCX 4016–treated groups. Platelet count was similar before the clamp in the four study groups and decreased slightly, but not significantly, after the clamp. Hematocrit values were similar at baseline in all study groups and remained unchanged after the clamp.

Bottom Line: 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.Pretreatment with aspirin, despite full inhibition of platelet COX-1, did not prevent it (-12.7 +/- 6.9 s, NS vs. placebo).On the contrary, pretreatment with the NO donor NCX 4016, alone or in combination with aspirin, suppressed platelet activation induced by acute hyperglycemia (NCX 4016 +10.5 +/- 8.3 s; NCX 4016 plus aspirin: +12.0 +/- 10.7 s, P < 0.05 vs. placebo for both).

View Article: PubMed Central - PubMed

Affiliation: Section of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Perugia, Italy. grespa@unipg.it

ABSTRACT

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 (basal closure time 63 +/- 7.1 s, after hyperglycemia 49.5 +/- 1.4 s, -13.5 +/- 6.3 s, P < 0.048). Pretreatment with aspirin, despite full inhibition of platelet COX-1, did not prevent it (-12.7 +/- 6.9 s, NS vs. placebo). On the contrary, pretreatment with the NO donor NCX 4016, alone or in combination with aspirin, suppressed platelet activation induced by acute hyperglycemia (NCX 4016 +10.5 +/- 8.3 s; NCX 4016 plus aspirin: +12.0 +/- 10.7 s, P < 0.05 vs. placebo for both). Other parameters of shear stress-dependent platelet activation were also more inhibited by NCX 4016 than by aspirin, despite lesser inhibition of COX-1.

Conclusions: Acute hyperglycemia-induced enhancement of platelet activation is resistant to aspirin; a NO-donating agent suppresses it. Therapeutic approaches aiming at a wider platelet inhibitory action than that exerted by aspirin may prove useful in patients with type 2 diabetes.

Show MeSH
Related in: MedlinePlus