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.