Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia

Abstract

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 activatorinhibitor-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. IntroductionType 2 diabetes is associated with an increased risk for thrombotic complications. 1 It has been estimated that 80% of diabetic patients die from acute arterial thrombosis, such as myocardial infarction and ischemic cerebrovascular events. 2 Apart from the accelerated development of atherosclerosis in patients with diabetes, these patients were also found to have an increased risk of thrombotic events, explained by an increased procoagulant activity combined with a decreased fibrinolytic capacity. 1 In addition, diabetic patients are prone to develop infectious diseases and more frequently die from infections than nondiabetic controls. 3 The enhanced infection risk is, at least in part, related to an impaired innate immune system. Concentrations of cytokines, molecules that orchestrate the innate immune response, are altered in diabetic patients, 4,5 and several functions of neutrophils, specialized in the killing of invading bacteria, are suppressed. 6 A prominent feature of type 2 diabetes is the concurrent existence of hyperglycemia and hyperinsulinemia. We recently demonstrated that hyperglycemia and hyperinsulinemia have differential and selective effects on the hemostatic balance in healthy humans. 7 In a strictly controlled setting, we showed that acute hyperglycemia activates coagulation independent of insulin levels, whereas hyperinsulinemia inhibits fibrinolysis irrespective of plasma glucose levels. 7 Inflammation and coagulation are tightly inte...

Insulin resistance in young, lean male subjects with essential hypertension

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High glucose modulates IL‐6 mediated immune homeostasis through impeding neutrophil extracellular trap formation

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“…It is established that occurrence of other diseases in TB patients is cardiac diseases, cancer, diabetes, various infections and toxicity of the drugs [7]. Diabetic patients are more prone to infections, because the high blood glucose levels compromise the immune system [8,9]. Up to 2% of TB patients can develop cardiovascular diseases [10].…”