Local insulin infusion stimulates expression of plasminogen activator inhibitor-1 and tissue-type plasminogen activator in normal subjects

Purpose: Plasma levels of plasminogen activator inhibitor-1 are increased in obesity, hypertension, and diabetes. Their correlation with insulin levels supports the hypothesis that hypofibrinolysis may affect the development of atherosclerotic complications in patients with insulin resistance. To investigate the effect of insulin on fibrinolysis, we evaluated levels of plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) antigens during insulin infusion in the forearm vascular beds of 8 healthy subjects. Materials and Methods: Insulin was infused in the brachial artery of each subject to raise local venous concentrations to approximately 100 μU/mL. Blood samples were obtained from the brachial artery and vein at baseline, after 30, 60, 90, and 120 minutes of infusion, and 30 minutes after the end of the infusion. Results: Following intra-arterial infusion of insulin, forearm blood flow (mean ± SD) increased progressively from 2.7 ± 0.6 to 4.0 ± 0.6 mL/dL/min (P<0.01) and did not return to baseline after the end of the infusion. Plasminogen activator inhibitor-1 balance increased (345 ± 160 versus 8 ± 152 fmol/dL/min, P<0.02) at 60 minutes, reaching baseline levels after the end of the infusion. After 90 minutes, tPA balance increased (40 ± 26 versus 7 ± 29 fmol/dL/min, P<0.01) with a profile similar to forearm blood flow. Conclusions: Local hyperinsulinemia induces regional vasodilation and expression of PAI-1 and tPA antigens. An alteration of this physiological process could be involved in the development of hypofibrinolysis and atherosclerosis in states of insulin resistance.