Platelet function in diabetes mellitus : studies on postprandial platelet activation and aspirin treatment

Sammanfattning: Diabetes mellitus (DM) is a prothrombotic disease which is associated with a high risk for cardiovascular events, especially in type 2 DM (T2DM). The aim of this work is to contribute to the improvement of cardiovascular risk in DM. Patients with DM have reduced responses to antiplatelet treatment with aspirin, perhaps due to an increased platelet turnover, and this is associated with a poor outcome. Postprandial hyperglycemia is an independent risk factor for cardiovascular complications. We compared the laboratory responses to twice daily dosing of aspirin 75 mg, the regular once daily dose of 75 mg or a higher once daily dose of 320 mg in an open cross-over study in 25 patients with T2DM and micro/macrovascular complications, We found an improved response to 75 mg twice daily as compared to both once daily doses using two whole blood methods; impedance platelet aggregometry and the IMPACT-R cone and platelet analyzer. Both patients with a high and low platelet turnover could benefit from twice daily dose of aspirin. The role of postprandial hyperglycemia in postprandial platelet activation was examined in a randomized cross-over study comparing premeal insulin (0.1 and 0.2 U/kg insulin aspart) and placebo in 18 patients with T2DM. Platelet activation was studied in the fasting state, before and after normalizing glucose levels, and 90 min after a carbohydrate rich meal. Although postprandial glucose levels decreased after insulin injection, platelet activation increased. Glucose normalization with IV insulin aspart before the meal also resulted in platelet activation mainly via the thromboxane pathway as studied with the thromboxane analogue U46619 using flow cytometry. The postprandial platelet activation was correlated directly to insulin levels and inversely to glucose levels. We therefore concluded that postprandial platelet activation in T2DM is related to insulin rather than to glucose levels. The role of insulin in postprandial platelet activation was further investigated by comparing T1DM (n=11) and T2DM (n=9), without premeal insulin before and after a carbohydrate rich meal. T1DM patients, who had very high postprandial glucose levels due to inability to secrete insulin, had no platelet activation after the meal. These findings further support the role of insulin in postprandial platelet activation. Microparticles derived from platelets, monocytes and endothelial cells were formed after a carbohydrate meal in both patients with T1DM and T2DM in the above study. The microparticles had a prothrombotic potential (thrombin generation assay) which was related to phosphatidylserine and not to tissue factor expression. As opposed to the importance of insulin in postprandial platelet activation seen in T2DM, the procoagulant microparticles increased similarly or even more in T1DM. Therefore microparticle release may be related to hyperglycemia rather than hyperinsulinemia. This work suggests that twice daily dosing can improve the response to low-dose aspirin treatment in T2DM which might improve cardiovascular prognosis, and that liberal usage of premeal insulin may not benefit patients with T2DM as it contributes to postprandial platelet activation, and insulin treatment has been related to increased cardiovascular risk in DM. Postprandial platelet activation does not occur without premeal insulin in T1DM but should also be studied after insulin. Prothrombotic microparticle release however occurs in both T1DM and T2DM after the meal.