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

Summary

The 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.

• References

• 1 Vague P, Juhan-Vague I, Aillaud MF, Badier C, Viard R, Alessi MC, Collen D. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level, and relative body weight in normal and obese subjects. Metabolism 1986; 35: 250-253
• 2 Landin K, Tengbom L, Smith U. Elevated fibrinogen and plasminogen activator inhibitor (PAI-1) in hypertension are related to metabolic risk factors for cardiovascular disease. J Intern Med 1990; 227: 273-278
• 3 Gram J, Jespersen J, Kold A. Effects of an oral antidiabetic drug on the fibrinolytic system of blood in insulin-treated diabetic patients. Metabolism 1988; 37: 937-943
• 4 Alessi MC, Juhan-Vague I, Kooistra T, Declerck PJ, Collen D. Insulin stimulates the synthesis of plasminogen activator inhibitor 1 by the human hepatocellular cell line Hep G2. Thromb Haemostas 1988; 60: 491-494
• 5 Feamey GR, Vincent CT, Chakrabarti R. Reduction of blood fibrinolytic activity in diabetes mellitus by insulin. Lancet 1959; 2: 1067
• 6 Hedlin AM. Insulin and blood fibrinolytic activity. Thromb Diath Haemorrh 1973; 29: 293-299
• 7 DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237: E214-E223
• 8 Landin K, Lonnroth P, Krotkiewski M, Holm G, Smith U. Increased insulin resistance and fat cell lipolysis in obese but not lean women with a high waist/hip ratio. Eur J Clin Invest 1990; 20: 530-535
• 9 Heding LG. Radioimmunological determination of human C-peptide in serum. Diabetologia 1975; 11: 541-548
• 10 Dole VP, Meinertz H. Microdetermination of long-chain fatty acids in plasma and tissues. J Biol Chem 1960; 235: 2595-2599
• 11 Chmielewska J, Rånby M, Wiman B. Evidence for a rapid inhibitor to tissue plasminogen activator in plasma. Thromb Res 1983; 31: 427-436
• 12 Hamsten A, Wiman B, deFaire U, Blombäck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-1563
• 13 Hamsten A, deFaire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9
• 14 Landin K, Stigendal L, Eriksson E, Krotkiewski M, Risberg B, Tengbom L, Smith U. Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1. Metabolism 1990; 39: 1044-1048
• 15 Kannel WB, Wolf PA, Verier J, McNamara PM. Epidemiologic assessment of the role of blood pressure in stroke: the Framingham study. J Am Med Assoc 1970; 214: 301-310
• 16 Larsson B, Svärdsudd K, Welin L, Wilhelmsen L, Bjorntorp P, Tibblin G. Abdominal adipose tissue distribution, obesity, and risk for cardiovascular disease and death: 13 year follow up of participants in the study of men bom in 1913. Br Med J 1984; 288: 1401-1404
• 17 Sundell B, Nilsson TK, Hallmans G, Hellsten G, Dahlen GH. Interrelationships between plasma levels of plasminogen activator inhibitor, tissue plasminogen activator, lipoprotein (a), and established cardiovascular risk factors in a North Swedish population. Atherosclerosis 1989; 80: 9-16
• 18 Pyorala K. Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: Results from two population studies in Finland. Diabetes Care 1979; 2: 131-141
• 19 Rowe JW, Young JB, Minaker KL, Stevens AL, Pallotta J, Lands-berg L. Effect of insulin and glucose infusions on sympathetic nervous system activity in normal man. Diabetes 1981; 30: 219-225
• 20 Gader AMA, Clarkson AR, Cash JD. The plasminogen activator and coagulation factor VIII responses to adrenaline, noradrenaline, isoprenaline and salbutamol in man. Thromb Res 1973; 2: 9-16
• 21 Smith D, Gilbert M, Owen WG. Tissue plasminogen activator release in vivo in response to vasoactive agents. Blood 1985; 66: 835-839
• 22 Biggs R, Macfarlane RG. Observations on fibrinolysis. Experimental activity produced by exercise or adrenaline. Lancet 1947; 1: 402-405
• 23 Lager I, Attvall S, Eriksson BM, von Schenck H, Smith U. Studies on the insulin-antagonistic effect of catecholamines in normal man. Evidence for the importance of (L-receptors. Diabetologia 1986; 29: 409-416