The Acute Effect of Insulin on Tissue Plasminogen Activator and Plasminogen Activator Inhibitor in Man

Abstract

SummaryThe present study was performed to elucidate the acute effect of insulin on levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor of endothelial cell type (PAI-1). Nine middle-aged, non-obese and non-smoking men were studied during a hyperinsulinemic, euglycemic glucose clamp for 2 h. Plasma insulin level during the clamp averaged 84 ± 12 mU/l and euglycemia was maintained at 4.9 ± 0.6 mmol/l. The t-PA activity gradually increased (75% mean increase after 2h, p <0.001) and the PAI-1 activity decreased (49% mean decrease after 2 h, p <0.001) during the clamp. t-PA activity decreased and PAI-1 activity increased after the insulin infusion was ceased, but they were still 48% higher and 38% lower, respectively, after 60 min. PAI-1 and t-PA activities were not affected by saline infusion for 2h.Thus, acute changes in the insulin levels lead to alterations rapid in the fibrinolytic system even when euglycemia is maintained. These effects may be induced by insulin itself or by the concomitant activation of the sympatho-adrenal system during the euglycemic clamp.

Hyperglycemia Stimulates Coagulation, Whereas Hyperinsulinemia Impairs Fibrinolysis in Healthy Humans

“…Although in rabbits, infusion of insulin increased PAI-1 activity (15), exogenous insulin administration under euglycemic and hyperglycemic conditions did not influence plasma PAI-1 activity in investigations in human subjects (12)(13)(14). Although in these human studies, plasma insulin concentrations were raised to ϳ575-650 pmol/l, these levels were maintained rather briefly, considering that insulin was infused for only 1-3 h; our investigation clearly shows that alterations in PAI-1 levels occur in a time-dependent way, with the strongest change recorded at the end of the 6-h observation period.…”

“…Several experimental studies have addressed the question of whether hyperglycemia or hyperinsulinemia per se influences fibrinolysis or coagulation (12)(13)(14)(15)(16)(17). These studies, in which plasma glucose and/or insulin levels were artificially increased by exogenous infusion, have been inconclusive, in particular, because in none of these studies were both plasma glucose and insulin concurrently maintained at either normal levels or at levels found in type 2 diabetes.…”

Fibrin(ogen) and diabetes mellitus: don't forget fibrinolysis

“…A number of studies have shown the correlation between high plasma level of PAI-1 and hyperinsulinism [26], a feature of NIDDM diabetes, obesity and possibly of IDDM patients on insulin treatment. In euglycaemic clamp studies, insulin infusion appeared to increase the plasma level of PAI-1 [27]. In order to rule out the contribution of hepatocytes to the release of PAI-1 in the systemic circulation and to assess the endothelial response to the infusion of insulin, we used a human model of 'functionally isolated' vascular district where the brachial artery and vein were cannulated, so that veno-arterial difference in PAI-1 concentration could reasonably represent the net production of endothelial PAI-1.…”

Plasminogen activator inhibitor 1: Mechanisms of its synergistic regulation by growth factors

“…PAI-1 expression is regulated by many hormones, cytokines and growth factors including insulin, transforming growth factor type beta (TGF-β), epidermal growth factor (EGF), basic fibroblast growth factor (FGF-2), insulin-like growth factor I (IGF-I) and tumor necrosis factor alpha (TNFα) Landin, Tengborn et al 1991;Schneider and Sobel 1991;Peiretti, Alessi et al 1997;Watanabe, Kurabayashi et al 2001). TGF-β and EGF cooperatively regulate PAI-1 expression .…”