Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia.
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 8 hours during clamp experiments in which either plasma glucose, insulin, both, or none was increased, depending on randomization. Target plasma concentrations were 5 versus 12 mM for glucose, and 100 versus 400 pmol/L for insulin. After 3 hours, 4 ng/kg Escherichia 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 < .001) and exaggerated coagulation (plasma concentrations of thrombin-antithrombin complexes and soluble tissue factor, both P < .001). Hyperinsulinemia attenuated fibrinolytic activity due to elevated plasminogen activator-inhibitor-1 levels (P < .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.
Stegenga
Michiel E
ME
Center for Infection and Immunity Amsterdam, Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. m.e.stegenga@amc.uva.nl
van der Crabben
Saskia N
SN
Blümer
Regje M E
RM
Levi
Marcel
M
Meijers
Joost C M
JC
Serlie
Mireille J
MJ
Tanck
Michael W T
MW
Sauerwein
Hans P
HP
van der Poll
Tom
T
D000328:Adult; D001777:Blood Coagulation; D015550:Cell Degranulation; D016207:Cytokines / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000276:immunology; D042783:Endothelial Cells / Q000502:physiology; D019446:Endotoxemia / Q000097:blood* / Q000150:complications* / Q000276:immunology; D004731:Endotoxins / Q000008:administration & dosage; D005342:Fibrinolysis; D015309:Glucose Clamp Technique; D006801:Humans; D006943:Hyperglycemia / Q000097:blood* / Q000150:complications* / Q000276:immunology; D006946:Hyperinsulinism / Q000097:blood* / Q000150:complications* / Q000276:immunology; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*
D016207:Cytokines; D004731:Endotoxins; D018836:Inflammation Mediators