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Blood, 1 July 2008, Vol. 112, No. 1, pp. 82-89.
Prepublished online as a Blood First Edition Paper on March 3, 2008; DOI 10.1182/blood-2007-11-121723.
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Submitted November 1, 2007
Accepted February 27, 2008
Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia
Michiel E Stegenga*, Saskia N van der Crabben, Regje ME Blumer, Marcel Levi, Joost CM Meijers, Mireille J Serlie, Michael WT Tanck, Hans P Sauerwein, and Tom van der Poll
Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
* Corresponding author; email: m.e.stegenga{at}amc.uva.nl.
Type 2 diabetes is associated with altered immune and hemostatic responses. We investigated the selective effects of hyperglycemia and hyperinsulinemia on innate immune, coagulation and fibrinolytic responses during systemic inflammation. Twenty-four healthy humans were studied for eight hours during clamp experiments in which either plasma glucose, insulin, both or none were increased, depending on randomization. Target plasma concentrations were 5 versus 12 mmol/L for glucose, and 100 versus 400 pmol/L for insulin. After three hours, 4 ng/kg of E. coli endotoxin was injected intravenously to induce a systemic inflammatory and procoagulant response. Endotoxin administration induced cytokine release, activation of neutrophils, endothelium and coagulation, and inhibition of fibrinolysis. Hyperglycemia reduced neutrophil degranulation (plasma elastase levels, P < 0.001), and exaggerated coagulation (plasma concentrations of thrombin-antithrombin complexes and soluble tissue factor, both P < 0.001). Hyperinsulinemia attenuated fibrinolytic activity due to elevated plasminogen activator-inhibitor-1 levels (P < 0.001). Endothelial cell activation markers and cytokine concentrations did not differ between clamps. We conclude that in humans with systemic inflammation induced by intravenous endotoxin administration hyperglycemia impairs neutrophil degranulation and potentiates coagulation, whereas hyperinsulinemia inhibits fibrinolysis. These data suggest that type 2 diabetes patients may be especially vulnerable to prothrombotic events during inflammatory states.
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