Hyperglycemia Stimulates Coagulation, Whereas Hyperinsulinemia Impairs Fibrinolysis in Healthy Humans

Abstract

Type 2 diabetes and insulin resistance syndromes are associated with an increased risk for cardiovascular and thrombotic complications. A disturbed balance between coagulation and fibrinolysis has been implicated in the pathogenesis hereof. To determine the selective effects of hyperglycemia and hyperinsulinemia on coagulation and fibrinolysis, six healthy humans were studied on four occasions for 6 h: 1) lower insulinemic-euglycemic clamp, 2) lower insulinemic-hyperglycemic clamp, 3) hyperinsulinemic-euglycemic clamp, and 4) hyperinsulinemic-hyperglycemic clamp. In the hyperglycemic clamps, target levels of plasma glucose were 12 versus 5 mmol/l in the normoglycemic clamps. In the hyperinsulinemic clamps, target plasma insulin levels were 400 versus 100 pmol/l in the lower insulinemic clamps. Hyperglycemia exerted a procoagulant effect irrespective of insulin levels, as reflected by mean twofold rises in thrombin-antithrombin complexes and soluble tissue factor, whereas hyperinsulinemia inhibited fibrinolysis irrespective of glucose levels, as reflected by a decrease in plasminogen activator activity levels due to a mean 2.5-fold rise in plasminogen activator inhibitor type 1. The differential effects of hyperglycemia and hyperinsulinemia suggest that patients with hyperglycemia due to insulin resistance are especially susceptible to thrombotic events by a concurrent insulin-driven impairment of fibrinolysis and a glucose-driven activation of coagulation.

Is polycystic ovary syndrome another risk factor for venous thromboembolism? United States, 2003–2008

“…27 Hyperinsulinemia 28 and lower sex hormone-binding globulin 29 have been shown to impair fibrinolysis by directly enhancing the secretions of PAI-1. 28 PAI-1 is the principal inhibitor of fibrinolysis and may contribute to the development of thrombosis. 28,29 From this logic, we speculate that the women in our study population with PCOS between the ages of 18-24 years may have increased levels of PAI-1 compared with the other age groups and thus have the highest probability of VTE.…”

“…28 PAI-1 is the principal inhibitor of fibrinolysis and may contribute to the development of thrombosis. 28,29 From this logic, we speculate that the women in our study population with PCOS between the ages of 18-24 years may have increased levels of PAI-1 compared with the other age groups and thus have the highest probability of VTE. Clinical studies are needed to test this hypothesis.…”

Tissue Factor and Cardiovascular Disease: Quo Vadis?

“…In diabetes, TF expression is increased either directly by elevated glucose levels, 99 hyperinsulinemia, 100 or alternatively via activation of NFκB through advanced glycation end-products (AGE) 101 or reactive oxygen species (ROS). 102 AGE stimulates NFκB via their membrane receptor (RAGE) while ROS directly activate the transcription factor.…”

Acute Hyperglycemia in Patients With Acute Myocardial Infarction

“…It has been reported that hyperglycemia elevates coagulant activation markers, including thrombin antithrombin complexes and soluble tissue factor, whereas hyperinsulinemia inhibits fibrinolysis. 27 Sakamoto et al 28 examined alternation of platelet aggregability during the OGTT. Platelet aggregability, defined as the number of small platelet aggregations, was measured with a laser-light scattering method.…”