Abstract
OBJECTIVE: Platelet aggregation responses to acetylsalicylic acid (ASA) show considerable interindividual variation, the causes of which are largely unknown. We determined whether variation in insulin action is associated with that of ASA on platelets.
SUBJECTS: In all, 10 nonobese (age 50±3 y, BMI 25±1 kg/m2) and 11 obese (age 52±2 y, BMI 32±1 kg/m2) subjects.
MEASUREMENTS: Insulin sensitivity of glucose uptake was determined by the euglycemic insulin clamp technique. Platelet aggregation responses to four doses of arachidonic acid (AA) and adenosine diphosphate (ADP) were assessed in platelet-rich plasma before and 1 h after ingestion of 50 mg ASA using Born's turbidometric aggregometer.
RESULTS: Whole-body insulin sensitivity (M-value 0–180 min) was 36% lower in the obese (4.5±0.6) than the nonobese (7.1±0.6 mg/kg min, P<0.01) group. Before ASA, all doses of AA induced complete aggregation. After ASA ingestion, ASA inhibited maximal aggregation more in the nonobese than the obese group at AA concentrations of 0.75, 1 and 1.5 mmol/l (P=0.016 for ANOVA). ADP-induced aggregation at high doses (2 and 3 μmol/l) was also less inhibited in the obese group. In vivo insulin sensitivity (r=−0.68, P<0.001 for 1 mmol/l AA) and BMI (r=0.58, P<0.01 for 1 mmol/l AA) were closely correlated with residual aggregation after ASA administration.
CONCLUSION: These data demonstrate that obese insulin-resistant subjects have a blunted response to platelet-inhibitory effect of ASA. If this blunted effect is of a single dose of ASA preserved in continuous use, it could contribute to the increased risk of atherothrombosis in insulin-resistant individuals.
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References
Kannel WBM . Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care 1979; 2: 120–126.
Haffner SML . Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339: 229–234.
Winocour PD . Platelet abnormalities in diabetes mellitus. Diabetes 1992; 41(Suppl 2): 26–31.
Jackson CA, Greaves M, Boulton AJ, Ward JD, Preston FE . Near-normal glycaemic control does not correct abnormal platelet reactivity in diabetes mellitus. Clin Sci (Colch) 1984; 67: 551–555.
Colwell JA, Sagel J, Crook L, Chambers A, Laimins M . Correlation of platelet aggregation, plasma factor activity, and megathrombocytes in diabetic subjects with and without vascular disease. Metabolism 1977; 26: 279–285.
Sagel J, Colwell JA, Crook L, Laimins M . Increased platelet aggregation in early diabetus mellitus. Ann Intern Med 1975; 82: 733–738.
Tschoepe D, Roesen P, Kaufmann L, Schauseil S, Kehrel B, Ostermann H, Gries FA . Evidence for abnormal platelet glycoprotein expression in diabetes mellitus. Eur J Clin Invest 1990; 20: 166–170.
Davi G, Catalano I, Averna M, Notarbartolo A, Strano A, Ciabattoni G, Patrono C . Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med 1990; 322: 1769–1774.
Aoki I, Shimoyama K, Aoki N, Homori M, Yanagisawa A, Nakahara K, Kawai Y, Kitamura SI, Ishikawa K . Platelet-dependent thrombin generation in patients with diabetes mellitus: effects of glycemic control on coagulability in diabetes. J Am Coll Cardiol 1996; 27: 560–566.
Tschope D, Rosen P, Gries FA . Increase in the cytosolic concentration of calcium in platelets of diabetics type II. Thromb Res 1991; 62: 421–428.
Jokl R, Klein RL, Lopes-Virella MF, Colwell JA . Release of platelet plasminogen activator inhibitor 1 in whole blood is increased in patients with type II diabetes. Diabetes Care 1995; 18: 1150–1155.
Knobler H, Savion N, Shenkman B, Kotev-Emeth S, Varon D . Shear-induced platelet adhesion and aggregation on subendothelium are increased in diabetic patients. Thromb Res 1998; 90: 181–190.
Rabini RA, Staffolani R, Fumelli P, Mutus B, Curatola G, Mazzanti L . Decreased nitric oxide synthase activity in platelets from IDDM and NIDDM patients. Diabetologia 1998; 41: 101–104.
Falcon C, Pfliegler G, Deckmyn H, Vermylen J . The platelet insulin receptor: detection, partial characterization, and search for a function. Biochem Biophys Res Commun 1988; 157: 1190–1196.
Trovati M, Mularoni EM, Burzacca S, Ponziani MC, Massucco P, Mattiello L, Piretto V, Cavalot F, Anfossi G . Impaired insulin-induced platelet antiaggregating effect in obesity and in obese NIDDM patients. Diabetes 1995; 44: 1318–1322.
Trovati M, Anfossi G, Cavalot F, Massucco P, Mularoni E, Emanuelli G . Insulin directly reduces platelet sensitivity to aggregating agents. Studies in vitro and in vivo. Diabetes 1988; 37: 780–786.
Westerbacka J, Yki-Jarvinen H, Turpeinen A, Rissanen A, Vehkavaara S, Syrjala M, Lassila R . Inhibition of platelet–collagen interaction: an in vivo action of insulin abolished by insulin resistance in obesity. Arterioscler Thromb Vasc Biol 2002; 22: 167–172.
Hiramatsu K, Nozaki H, Arimori S . Reduction of platelet aggregation induced by euglycaemic insulin clamp. Diabetologia 1987; 30: 310–313.
Trovati M, Anfossi G, Massucco P, Mattiello L, Costamagna C, Piretto V, Mularoni E, Cavalot F, Bosia A, Ghigo D . Insulin stimulates nitric oxide synthesis in human platelets and, through nitric oxide, increases platelet concentrations of both guanosine-3′,5′-cyclic monophosphate and adenosine-3′,5′-cyclic monophosphate. Diabetes 1997; 46: 742–749.
Anfossi G, Mularoni EM, Burzacca S, Ponziani MC, Massucco P, Mattiello L, Cavalot F, Trovati M . Platelet resistance to nitrates in obesity and obese NIDDM, and normal platelet sensitivity to both insulin and nitrates in lean NIDDM. Diabetes Care 1998; 21: 121–126.
Schror K . Aspirin and platelets: the antiplatelet action of aspirin and its role in thrombosis treatment and prophylaxis. Semin Thromb Hemostasis 1997; 23: 349–356.
Pedersen AK, FitzGerald GA . Dose-related kinetics of aspirin. Presystemic acetylation of platelet cyclooxygenase. N Engl J Med 1984; 311: 1206–1211.
AnonymousAspirin therapy in diabetes. American Diabetes Association. Diabetes Care 1997; 20: 1772–1773.
Helgason CM, Bolin KM, Hoff JA, Winkler SR, Mangat A, Tortorice KL, Brace LD . Development of aspirin resistance in persons with previous ischemic stroke. Stroke 1994; 25: 2331–2336.
Kawasaki T, Ozeki Y, Igawa T, Kambayashi J . Increased platelet sensitivity to collagen in individuals resistant to low-dose aspirin. Stroke 2000; 31: 591–595.
Valles J, Santos MT, Aznar J, Osa A, Lago A, Cosin J, Sanchez E, Broekman MJ, Marcus AJ . Erythrocyte promotion of platelet reactivity decreases the effectiveness of aspirin as an antithrombotic therapeutic modality: the effect of low-dose aspirin is less than optimal in patients with vascular disease due to prothrombotic effects of erythrocytes on platelet reactivity. Circulation 1998; 97: 350–355.
Pyorala M, Miettinen H, Halonen P, Laakso M, Pyorala K . Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Arterioscler Thromb Vasc Biol 2000; 20: 538–544.
DeFronzo RA, Tobin JD, Andres R . Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237: E214–E223.
Utriainen T, Malmström R, Mäkimattila S, Yki-Järvinen H . Methodological aspects, dose-response characteristics and causes of interindividual variation in insulin stimulation of limb blood flow in normal subjects. Diabetologia 1995; 38: 555–564.
Born GVR . Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962; 194: 927–929.
Kadish AH, Hall DA . A new method for the continuous monitoring of blood glucose by measurement of dissolved oxygen. Clin Chem 1965; 11: 869–875.
Desbuquois B, Aurbach GD . Use of polyethylene glycol to separate free and antibody-bound peptide hormones in radioimmunoassay. J Clin Endocrinol Metab 1971; 33: 732–738.
Vinik AI, Erbas T, Park TS, Nolan R, Pittenger GL . Platelet dysfunction in type 2 diabetes. Diabetes Care 2001; 24: 1476–1485.
Davi G, Ciabattoni G, Consoli A, Mezzetti A, Falco A, Santarone S, Pennese E, Vitacolonna E, Bucciarelli T, Costantini F, Capani F, Patrono C . In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation 1999; 99: 224–229.
Csiszar A, Stef G, Pacher P, Ungvari Z . Oxidative stress-induced isoprostane formation may contribute to aspirin resistance in platelets. Prostaglandins Leukotr Essent Fatty Acids 2002; 66: 557–558.
Cayatte AJ, Du Y, Oliver-Krasinski J, Lavielle G, Verbeuren TJ, Cohen RA . The thromboxane receptor antagonist S18886 but not aspirin inhibits atherogenesis in apo E-deficient mice: evidence that eicosanoids other than thromboxane contribute to atherosclerosis. Arterioscler Thromb Vasc Biol 2000; 20: 1724–1728.
Makimattila S, Liu ML, Vakkilainen J, Schlenzka A, Lahdenpera S, Syvanne M, Mantysaari M, Summanen P, Bergholm R, Taskinen MR, Yki-Jarvinen H . Impaired endothelium-dependent vasodilation in type 2 diabetes. Relation to LDL size, oxidized LDL, and antioxidants. Diabetes Care 1999; 22: 973–981.
Acknowledgements
Supported by grants from the Academy of Finland (Hannele Yki-Järvinen, Jukka Westerbacka), the Finnish Diabetes Research Foundation (Jukka Westerbacka), Liv och Hälsa (Hannele Yki-Järvinen), the Juselius (Hannele Yki-Järvinen) and Novo Nordisk (Hannele Yki-Järvinen), Foundations.
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Tamminen, M., Lassila, R., Westerbacka, J. et al. Obesity is associated with impaired platelet-inhibitory effect of acetylsalicylic acid in nondiabetic subjects. Int J Obes 27, 907–911 (2003). https://doi.org/10.1038/sj.ijo.0802312
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DOI: https://doi.org/10.1038/sj.ijo.0802312
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