Download PDF
Thromb Haemost 1995; 73(02): 261-267
DOI: 10.1055/s-0038-1653762
Original Article
Fibrinolysis
Schattauer GmbH Stuttgart

Determinants of Plasminogen Activator Inhibitor-1 Activity in Survivors of Myocardial Infarction

Rosaire P Gray
The Department of Medicine, University College London Medical School, London, UK
,
Vidya Mohamed-Ali
The Department of Medicine, University College London Medical School, London, UK
,
David L H Patterson
1   The Department of Cardiology, Whittington Hospital, London, UK
,
John S Yudkin
The Department of Medicine, University College London Medical School, London, UK
› Author Affiliations
Further Information

Publication History

Received 19 April 1994

Accepted after resubmission 20 October 1994

Publication Date:
26 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

A significant relationship has been described between plasminogen activator inhibitor-1 (PAI-1) and plasma insulin concentrations. However, most radioimmunoassays (RIA) substantially overestimate plasma insulin concentrations because of cross reaction with proinsulin-like molecules and it has been proposed that proinsulin-like molecules may be important determinants of PAI-1 activity. We measured fasting plasma immunoreactive insulin by conventional RIA, fasting plasma insulin (EIMA) by specific two site immuno-enzymometric assay, and intact proinsulin and des-31,32-proinsulin by two site immunoradiometric assay (IRMA) in 74 (50 nondiabetic and 24 diabetic) subjects who had survived a myocardial infarction between 6 and 24 months previously. In univariate analysis, PAI-1 activity correlated with serum triglycerides (rs=0.43; p <0.0001), insulin sensitivity (rs = -0.30; p = 0.004), and immunoreactive insulin (rs = 0.45; p <0.0001). However, the relationship between PAI-1 activity and plasma specific insulin (IEMA) was weaker (rs = 0.24; p = 0.019) than those with intact proinsulin (rs = 0.53; p <0.0001) and des-31,32-proinsulin (rs = 0.54; p <0.0001) despite the low concentrations of these proinsulin-like molecules. In multiple regression analysis, only des-31,32-proinsulin (p = 0.001) and serum triglycerides (p = 0.013) were significant determinants of PAI-1 activity. In conclusion, these results suggest that proinsulin-like molecules and serum triglycerides are important determinants of PAI-1 activity in survivors of myocardial infarction.

 

  • 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
    CrossrefPubMedGoogle Scholar
  • 2 Juhan-Vague I, Vague P, Alessi MC, Badier C, Valadier J, Aillaud MF, Atlan C. Relationships between plasma insulin, triglyceride, body mass index and plasminogen activator inhibitor l. DiabetMetab 1987; 13: 331-336
    PubMedGoogle Scholar
  • 3 Vague P, Juhan-Vague I, Chabert V, Alessi MC, Atlan C. Fat distribution and plasminogen activator inhibitor activity in non diabetic obese women. Metabolism 1989; 38: 913-915
    CrossrefPubMedGoogle Scholar
  • 4 Juhan-Vague I, Alessi MC, Joly P, Thirion X, Vague P, Declerck PJ, Serra- dimigni A, Collen D. Plasma plasminogen activator inhibitor-1 in angina pectoris: influence of plasma insulin and acute phase response. Arteriosclerosis 1989; 9: 362-367
    CrossrefPubMedGoogle Scholar
  • 5 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 Int Med 1990; 227: 273-278
    CrossrefPubMedGoogle Scholar
  • 6 Juhan-Vague I, Roul C, Alessi MC, Ardissone JP, Heim M, Vague P. Increased plasminogen activator inhibitor activity in non insulin dependent diabetic patients - relationship with plasma insulin. Thromb Haemost 1989; 61: 370-373
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Aimer L, Ohlin H. Elevated levels of the rapid inhibitor of plasminogen activator (t-PAI) in acute myocardial infarction. Thromb Res 1987; 47: 335-339
    CrossrefPubMedGoogle Scholar
  • 8 Gray RP, Yudkin JS, Patterson DL H. Plasminogen activator inhibitor - a risk factor for myocardial infarction in diabetic subjects. Br Heart J 1993; 69: 228-232
    CrossrefPubMedGoogle Scholar
  • 9 Gray RP, Yudkin JS, Patterson DL H. Enzymatic evidence of impaired reperfusion in diabetic subjects after thrombolytic therapy for acute myocardial infarction - a role for plasminogen activator inhibitor. Br Heart J 1993; 70: 530-536
    CrossrefPubMedGoogle Scholar
  • 10 Barbash GI, Hod H, Rod A, Miller HI, Rath S, Har Zahav Y, Modan M, Zivelin A, Laniado S, Seligsohn U. Correlation of baseline plasminogen activator inhibitor activity with patency of the infarct related artery after thrombolytic therapy in acute myocardial infarction. Am J Cardiol 1989; 64: 1231-1235
    CrossrefPubMedGoogle Scholar
  • 11 Sane DC, Stump DC, Topol EJ, Sigmon KN, Kereiakes DJ, George BS, Mantell SJ, Macy E, Collen D, Califf RM. Correlation between baseline plasminogen activator inhibitor levels and clinical outcome during therapy with tissue plasminogen activator for acute myocardial infarction. Thromb Haemost 1991; 65: 275-279
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Hamsten A, De Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blombach M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 1: 3-8
    PubMedGoogle Scholar
  • 13 Juhan-Vague I, Thompson SG, Jespersen J. Involvement of the haemostatic system in the insulin resistance syndrome. A study of 1500 patients with angina pectoris Arteriosclerosis and Thrombosis 1993; 13: 1865-1873
    CrossrefPubMedGoogle Scholar
  • 14 Sobey WJ, Beer SF, Carrington CA, Clark PM S, Frank BH, Gray P, Luzio SD, Owens DR, Schneider AE, Siddle K, Temple RC, Hales CN. Sensitive and specific two site immunoradiometric assays for human insulin, proinsulin, 65-66 split and 32-33 split proinsulins. Biochem J 1989; 260: 535-541
    CrossrefPubMedGoogle Scholar
  • 15 Temple RC, Carrington CA, Luzio SD, Owens DR, Schneider AE, Sobey WJ, Hales CN. Insulin deficiency in non insulin dependent diabetes. Lancet 1989; 1: 293-295
    PubMedGoogle Scholar
  • 16 Yoshioka N, Kuzuya T, Matsuda A, Taniguchi M, Iwamoto Y. Serum proinsulin levels at fasting and after oral glucose load in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1988; 31: 355-360
    CrossrefPubMedGoogle Scholar
  • 17 Ward WK, LeCava EC, Paquette TL, Beard JC, Wallum BJ, Porte Jr D. Disproportionate elevation of immunoreactive proinsulin in Type 2 (noninsulin-dependent) diabetes mellitus and in experimental insulin resistance. Diabetologia 1987; 30: 698-702
    CrossrefPubMedGoogle Scholar
  • 18 Temple RC, Clark PM S, Nagi DK, Schneider A, Yudkin JS, Hales CN. Radioimmunoassay may overestimate insulin in non insulin dependent diabetics. Clin Endocrinol 1990; 32: 689-693
    CrossrefPubMedGoogle Scholar
  • 19 Nagi DK, Hendra TJ, Ryle AJ, Cooper TM, Temple RC, Clark PM S, Schneider AE, Hales CN, Yudkin JS. The relationships of concentrations of insulin, intact proinsulin and 32-33 split proinsulin with cardiovascular risk factors in type 2 (non insulin dependent) diabetic subjects. Diabetologia 1990; 33: 532-537
    CrossrefPubMedGoogle Scholar
  • 20 Sorge F, Schwartzkopff W, Neuhaus GA. Insulin response to oral glucose load in patients with a previous myocardial infarction and in patients with peripheral vascular disease: hyperinsulinism and its relationships to hyper- triglyceridaemia and overweight. Diabetes 1976; 25: 586-594
    CrossrefPubMedGoogle Scholar
  • 21 Larsen S, Lauritsen KB, Christiansen I. Oral glucose tolerance, insulin and gastric inhibitory polypeptide secretion in patients recovered from acute myocardial infarction. Diabetologia 1981; 21: 235-236
    PubMedGoogle Scholar
  • 22 Hamsten A, Efendic S, Walldius G, Szamosi A, de Faire U. Glucose tolerance and insulin response to glucose in non diabetic young male survivors of mycocardial infarction. Am Heart J 1987; 113: 917-927
    CrossrefPubMedGoogle Scholar
  • 23 Gray RP, Patterson DL H, Yudkin JS. Plasminogen activator inhibitor activity in diabetic and non diabetic survivors of myocardial infarction. Arteriosclerosis and Thrombosis 1993; 13: 415-420
    CrossrefPubMedGoogle Scholar
  • 24 WHO Regional Office for Europe. Public health in Europe 5. Myocardial infarction community registers. Annexe 1; Copenhagen: 1976
    Google Scholar
  • 25 Oswald GA, Yudkin JS. Hyperglycaemia following acute myocardial infarction: the contribution of undiagnosed diabetes. Diabetic Medicine 1987; 4: 68-70
    CrossrefPubMedGoogle Scholar
  • 26 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502
    CrossrefPubMedGoogle Scholar
  • 27 Mohamed-Ali V, Yudkin JS. An end point amplified enzymoimmunoassay (IEMA) specific for human insulin. Clinical Science 1992; 82 suppl (Suppl. 27) 4P (abstr)
    PubMedGoogle Scholar
  • 28 Mohamed-Ali V, Yudkin JS. Simple and highly sensitive microplate immunoradiometric assays (IRMAs) for intact proinsulin and des-31, 32-proinsulin. Diabetic Medicine 1993; 10 suppl (Suppl. 01) P67 (abstr)
    PubMedGoogle Scholar
  • 29 Stanley CJ, Johannsson A, Self CH. Enzyme amplification can enhance both the speed and the sensitivity of immunoassays. J Immunol Methods 1985; 83: 89-95
    CrossrefPubMedGoogle Scholar
  • 30 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta cell function from fasting glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419
    CrossrefPubMedGoogle Scholar
  • 31 Rao CR. Homogeneity of variances and correlations,. In: Advanced Statistical Methods in Biometric Research. New York: John Wiley ∆ Sons Inc; pp 230-235
    Google Scholar
  • 31 World Health Organisation. Diabetes Mellitus: report of a WHO Study Group. Technical report Series No 727, Geneva, WHO. 1985
    PubMedGoogle Scholar
  • 33 Gough SC L, Rice PJ S, McCormack L, Chapman C, Grant PJ. The relationship between plasminogen activator inhibitor and insulin resistance in newly diagnosed type 2 diabetes mellitus. Diabetic Medicine 1993; 10: 638-642
    CrossrefPubMedGoogle Scholar
  • 34 Asplund-Carlson A, Hamsten A, Wiman B, Carlson LA. Relationship between plasma plasminogen activator inhibitor-1 activity and VLDL triglyceride concentration, insulin levels and insulin sensitivity: studies in randomly selected normo- and hypertriglyceridaemic men. Diabetologia 1993; 36: 817-825
    CrossrefPubMedGoogle Scholar
  • 35 Landin K, Stigendal L, Eriksson E, Krotkiewski M, Risberg BO, Tengbom L, Smith U. Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1. Metabolism 1990; 39: 1044-1048
    CrossrefPubMedGoogle Scholar
  • 36 Gram G, Kluft C, Jespersen J. Depression of tissue plasminogen activator (t-PA) activity and rise of t-PA inhibition and acute phase reactants in blood of patients with acute myocardial infarction (AMI). Thromb Haemost 1987; 58: 817-821
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Juhan-Vague I, Vague P. Interrelations between carbohydrates, lipids, and the haemostatic system in relation to the risk of thrombotic and cardiovascular disease. Am J Obstet Gynecol 1990; 163: 313-315
    CrossrefPubMedGoogle Scholar
  • 38 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 Haemost 1988; 60: 491-494
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Kooistra T, Bosma PJ, Tons HA M, van den Berg AP, Meyer P, Princen HM G. Plasminogen activator inhibitor 1: biosynthesis and mRNA level are increased by insulin in cultured human hepatocytes. Thromb Haemost 1989; 62: 723-728
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Nordt TK, Schneider DJ, Sobel BE. Augmentation of the synthesis of plasminogen activator inhibitor type-1 by precursors of insulin: a potential risk factor for vascular disease. Circulation 1994; 89: 321-330
    CrossrefPubMedGoogle Scholar
  • 41 Gris JC, Schved JF, Feugeas O, Aguilar-Martinez P, Armaud A, Sanchez N, Sarlat C. Impact of smoking, physical training and weight reduction on FVII, PAI-1 and haemostatic markers in sedentary men. Thromb Haemost 1990; 64: 516-520
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Estelles A, Aznar J, Tormo G, Sapnea P, Tormo V, Espana F. Influence of a rehabilitation sports program on the fibrinolytic activity of patients after myocardial infarction. Thromb Res 1989; 55: 203-212
    CrossrefPubMedGoogle Scholar
  • 43 Grant PJ, Stickland MH, Booth NA, Prentice CR M. Metformin causes a reduction in basal and post venous occlusion plasminogen activator inhibitor- 1 in type 2 diabetic patients. Diabetic Medicine 1991; 8: 361-365
    CrossrefPubMedGoogle Scholar
  • 44 Nagi DK, Yudkin JS. The effects of metformin on insulin resistance, risk factors for cardiovascular disease and plasminogen activator inhibitor (PAI-1) in non insulin dependent diabetic (NIDDM) subjects. A study of two ethnic groups Diabetes Care 1993; 16: 621-629
    CrossrefPubMedGoogle Scholar
  • 45 Grant PJ, Kruithof EK O, Felley CP, Felber JP, Bachmann F. Short term infusions of insulin, triacylglycerol and glucose do not cause acute increases in plasminogen activator inhibitor-1 concentrations in man. Clinical Science 1990; 79: 513-516
    CrossrefPubMedGoogle Scholar
  • 46 Vuorinen-Markkola H, Puhakainen I, Yki-Jarvinen H. No evidence for short term regulation of plasminogen activator inhibitor activity by insulin in man. Thromb Haemost 1992; 67: 117-120
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Landin K, Tengbom L, Chmielewska J, von Schenck H, Smit U. The acute effect of insulin on tissue plasminogen activator and plasminogen activator inhibitor in man. Thromb Haemost 1991; 65: 130-133
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Potter van Loon BJ, Kluft C, Radder JK, Blankenstein MA, Meinders AE. The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance. Metabolism 1993; 42: 945-949
    CrossrefPubMedGoogle Scholar
  • 49 Olefsky JM, Farquhar JW, Reaven GM. Reappraisal of the role of insulin in hypertriglyceridemia. Am J Med 1974; 57: 551-560
    CrossrefPubMedGoogle Scholar
  • 50 Tobey TA, Greenfield M, Kraemer F, Reaven GM. Relationship between insulin resistance, insulin secretion, very low density lipoprotein kineticsand plasma triglyceride levels in normotriglyceridemic men. Metabolism 1981; 30: 165-171
    CrossrefPubMedGoogle Scholar
  • 51 Stiko-Rahm A, Wiman B, Hamsten A, Nilsson J. Secretion of plasminogen activator inhibitor-1 from cultured human umbilical vein endothelial cells is induced by very low density lipoprotein. Arteriosclerosis 1990; 10: 1067-1073
    CrossrefPubMedGoogle Scholar
  • 52 Davies MJ, Metcalfe J, Gray IP, Day JL, Hales CN. Insulin deficiency rather than hyperinsulinaemia in newly diagnosed type 2 diabetes mellitus. Diabetic Medicine 1993; 10: 305-312
    CrossrefPubMedGoogle Scholar
  • 53 Davies MJ, Rayman G, Gray IP, Day JL, Hales CN. Insulin deficiency and increased plasma concentrations of intact and 32/33 split proinsulin in subjects with impaired glucose tolerance. Diabetic Medicine 1993; 10: 313-320
    CrossrefPubMedGoogle Scholar
  • 54 Haffner SM, Mykkanen L, Stern MP, Valdez RA, Heisserman JA, Bowsher RR. Relationship of proinsulin and insulin to cardiovascular risk factors in non diabetic subjects. Diabetes 1993; 42: 1297-1302
    CrossrefPubMedGoogle Scholar
  • 55 Mohamed-Ali V, Gould MM, Goubet S, Yudkin JS. The relationship between insulin, intact proinsulin and des-31, 32-proinsulin and other cardiovascular risk factors in non-diabetic patients. Diabetic Med 1993; 10 suppl (Suppl. 03) S36
    PubMedGoogle Scholar
  • 56 Jain SK, Nagi DK, Slavin BM, Lumb PJ, Yudkin JS. Insulin therapy in type 2 diabetic subjects supresses plasminogen activator inhibitor (PAI-1) activity and proinsulin-like molecules independently of glycaemic control. Diabetic Medicine 1993; 10: 27-32
    CrossrefPubMedGoogle Scholar
  • 57 Peavy D, Abram JD, Frank BH, Duckworth WC. In vitro activity of biosynthetic human proinsulin. Receptor binding and biologic potency of proinsulin and insulin in isolated rat adipocytes Diabetes 1984; 33: 1062-1067
    CrossrefPubMedGoogle Scholar
  • 58 Ciaraldi TP, Brady D. Comparisons of insulin and biosynthetic human proinsulin actions in cultured hepatocytes. Horm Metab Res 1990; 22: 283-288
    Article in Thieme ConnectPubMedGoogle Scholar
  • 59 Probst I, Hartmann H, Jungermann K, Crutzfeldt W. Insulin-like action of proinsulin on rat liver carbohydrate metabolism in vitro. Diabetes 1985; 34: 415-419
    CrossrefPubMedGoogle Scholar
  • 60 Angius L, Chowdhury MH, Davis SN, Alberti KG M M. Regulation of keto- genesis, gluconeogenesis, and glycogen synthesis by insulin and proinsulin in rat hepatocyte monolayer cultures. Diabetes 1986; 35: 1286-1293
    CrossrefPubMedGoogle Scholar
  • 61 Peavy DE, Brunner MR, Duckworth WC, Hooker CS, Frank BH. Receptor binding and biological potency of several split forms (conversion intermediates) of human proinsulin: studies in cultured 1M -9 lymphocytes and in vivo and in vitro in rats. J Biol Chem 1985; 260: 13989-13994
    PubMedGoogle Scholar
  • 62 Gruppuso PA, Frank BH, Schwartz R. Binding of proinsulin and proinsulin conversion intermediates to human placental insulin-like growth factor-1 receptors. J Clin Endocrinol Metab 1988; 67: 194-197
    CrossrefPubMedGoogle Scholar
  • 63 Burguera B, Frank BH, Di Marchi R, Long S, Caro JF. The interaction of proinsulin with the insulin-like growth factor-1 receptor in human liver, muscle, and adipose tissue. J Clin Endocrinol Metab 191 72: 1238-1241
    PubMedGoogle Scholar
  • 64 Schneider DS, Nordt TK, Sobel BE. Stimulation by proinsulin of expression of plasminogen activator inhibitor type-1 in endothelial cells. Diabetes 1992; 41: 890-895
    CrossrefPubMedGoogle Scholar
  • 65 Panahloo A, Mohamed-Ali V, Lane A, Green F, Humphries S, Yudkin JS. Polymorphism in the promotor of the plasminogen activator inhibitor-1 (PAI-1) gene as a strong determinant of PAI- activity in non-insulin dependent diabetes. Diabetes 1994; 43 suppl (Suppl. 01) 35A
    PubMedGoogle Scholar
  • 66 Hales CN, Barker DJ P. Type 2 (non insulin dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992; 35: 595-601
    CrossrefPubMedGoogle Scholar