Environmental and Genetic Factors in Relation to Elevated Circulating Levels of Plasminogen Activator Inhibitor-1 in Caucasian Patients with Non-Insulin-Dependent Diabetes Mellitus

Summary

To investigate the interaction of metabolic and genetic factors in relation to PAI-1, genotype was determined at a 4G/5G polymorphism in the PAI-1 gene promoter and at a Hind III RFLP of the PAI-1 gene in 189 Caucasian NIDDM patients. PAI-1 levels were equivalent in each genotype group and PAI-1 activity correlated with fasting insulin (r = 0.45), triglyceride (r = 0.39) body mass index (r = 0.44), cholesterol (r = 0.17) and glucose (r = 0.15). The regression slope (B) of PAI-1 activity on triglycerides was steeper in the 4G/4G group than the other two groups: 4G/4G B = 0.91, r = 0.62; 4G/5G B = 0.36, r = 0.27; 5G/5G B = 0.31, r = 0.29 (difference between slopes p = 0.02) and the association between PAI-1 activity and glucose remained only in the 4G/4G group (r = 0.35). These results confirm the association of PAI-1 levels with the features of insulin resistance and indicate that the association between PAI-1 levels and both triglyceride and glucose is influenced by genotype in the region of the PAI-1 gene promoter.

• References

• 1 Kannal WB, McGee DL. Diabetes and cardiovascular disease, the Framingham Study. Jama 1979; 241: 2035-2038
• 2 Multiple Risk Factor Intervention Trial (MRFIT) Research Group. Multiple risk factor intervention trial: risk factor changes and mortality results. JAMA 1982; 248: 1465-1477
• 3 Pydörälä 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
• 4 Walmsley D, Hampton KK, Grant PJ. Contrasting fibrinolytic responses in type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes. Diabet Med 1991; 8: 954-959
• 5 Auwerx J, Bouillon R, Cullen D, Geboers J. Tissue-type plasminogen activator antigen and plasminogen activator inhibitor in diabetes mellitus. Arteriosclerosis 1988; 8: 68-72
• 6 Garefa Frade LJ, de la CalleH, Torrado MC, Lara JL, Cuellar L, Garcia Avello A. Hypofibrinolysis associated with vasculopathy in non insulin dependent diabetes mellitus. Thromb Res 1990; 59: 5l-59
• 7 Gough SC L, Rice PJ S, McCormack L, Chapman C, Grant PJ. The relationship between plasminogen activator inhibitor-1 and insulin resistance in newly diagnosed type 2 diabetes mellitus. Diabet Med 1993; 10: 638-642
• 8 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
• 9 Smith EB. Fibrinogen, fibrin and fibrin degradation products in relation to atherosclerosis. Clin Haematol 1986; 15: 355-370
• 10 Landin K, Stigendal L, Eriksson E, Krotkiewski M, Risberg B, Tengborn L, Smith U. Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1. Metabolism 1990; 39: 1044-1048
• 11 Landin K, Tengborn L, Smith U. Elevated fibrinogen and plasminogen activator inhibitors (PAN) in hypertension are related to metabolic risk factors for cardiovascular disease. J Int Med 1990; 227: 273-278
• 12 Potter van Loon BJ, Kluft K, Raadder JK, Blankenstein MA, Meinders AE. The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance. Metabolism 1993; 42: 945-949
• 13 Juhan-Vague I, Alessi MC, Joly P, Thirion W, Vague P, Declerck PJ, Serradimigni A, Collen D. Plasma plasminogen activator inhibitor-1 in angina pectoris. Influence of plasma insulin and acute phase-response Arteriosclerosis 1989; 9: 362-367
• 14 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 1. Diabete Metab 1987; 13: 331-336
• 15 Mehta J, Mehta P, Lawson D, Saldeen T. Plasma tissue plasminogen activator inhibitor levels in coronary artery disease: Correlations with age and triglyceride concentrations. J Am Coll Cardiol 1987; 9: 263-268
• 16 Hamsten A, de Faire U, Walldius G, Dahlén G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: Risk for recurrent myocardial infarction. Lancet 1987; 2: 3-9
• 17 Sundell IB, 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 Juhan-Vague I, Valadier J, Alessi MC, Aillaud MF, Ansaldi J, Philip-Joet C, Holvoet P, Serradimigni A, Collen D. Deficient t-PA release in patients with spontaneous or recurrent deep venous thrombosis. Thromb Haemost 1987; 57: 67-72
• 19 Mussoni L, Mannucci L, Sirtori M, Camera M, Maderna P, Sironi L, Tremoli E. Hypertriglyceridemia and regulation of fibrinolytic activity. Arterioscler Thromb 1992; 12: 19-27
• 20 Maiello M, Boeri D, Podesta F, Cagliero E, Vichi M, Odetti P, Adezati L, Lorenzi M. Increased expression of tissue plasminogen activator and its inhibitor and reduced fibrinolytic potential of human endothelial cells cultured in elevated glucose. Diabetes 1992; 41: 1009-1015
• 21 Nordt TK, Klassen KJ, Schneider DJ, Sobel BE. Augmentation of synthesis of plasminogen activator inhibitor type-1 in arterial endothelial cells by glucose and its implications for local fibrinolysis. Arterioscler Thromb 1993; 13: 1822-1828
• 22 Gunnarsson R, Nyman D, Wålinder O, üstman J. Fibrinolytic activity and diabetes control - Evidence for a relationship. A preliminary report Acta Med Scand Suppl 1980; 639: 23-24
• 23 van Wersch JW J, Donders SH J, Westerhuis LWJJM, Venekamp WJRR. Microalbuminuria in diabetic patients: relationship to lipid, glycomctabolic, coagulation and fibrinolysis parameters. Eur J Clin Chem Clin Biochem 1991; 29: 493-498
• 24 Dawson S, Hamsten A, Wiman B, Henney A, Humphries S. Genetic variation at the plasminogen activator inhibitor-1 locus is associated with altered levels of plasma plasminogen activator inhibitor-1 activity. Arterioscler Thromb 1991; 2: 183-190
• 25 Dawson S, Wiman B, Hamsten A, Green F, Humphries S, Henney A. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-I) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993; 268: 10739-10745
• 26 Mansfield MW, Stickland MH, Carter A, Grant PJ. Polymorphisms of the plasminogen activator inhibitor-1 gene in type I and type 2 diabetes and in patients with diabetic retinopathy. Thromb Haemost 1994; 71: 731-736
• 27 Falk G, Svensson II, Almqvist A, Wiman B. Allele specific PCR for detection of a sequence polymorphism in the promoter region of the plasminogen activator inhibitor-1 (PAI-I) gene (abstract). Fibrinolysis 1994; 8 Suppl (Suppl. 01) 45
• 28 Armitage P, Berry G. Statistical methods in medical research. 2nd. Edn Blackwell; Oxford,UK,: 1987. pp 273-282
• 29 Juhan-Vague I, Alessi MC. Plasminogen activator inhibitor 1 and athero-thrombosis. Thromb Haemost 1993; 70: 138-143
• 30 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
• 31 Grant PJ, Ruegg M, Medcalf RL. Basal expression and insulin-mediated induction of PAI-1 mRNA in Hep G2 cells. Fibrinolysis 1991; 5: 81-86
• 32 Kooistra T, Bosma PJ, Tons HAM, van den Berg AP, Meyer P, Princen HMG. Plasminogen activator inhibitor 1 Biosynthesis and mRNA level are increased by insulin in cultured human hepatocytes. Thromb Haemost 1989; 62: 723-728
• 33 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. Clin Sci 1990; 79: 513-516
• 34 Potter van Loon BJ, deBart AC W, Radder JK, Frölich M, Kluft C, Meinders AE. Acute exogenous hyperinsulinaemia does not result in elevation of plasma plasminogen activator inhibitor-1 (PAI-1) in humans. Fibrinolysis 1990; (Suppl. 04) Suppl 2: 93-94
• 35 Landin K, Tengborn L, Chmielewska J, von Schenck H, Smith U. The acute effect of insulin on tissue plasminogen activator and plasminogen activator inhibitor in man. Thromb Haemost 1991; 65: 130-133
• 36 McCormack L, Stickland MH, Grant PJ. Plasminogen activator inhibitor-1 antigen concentrations during insulin and oral glucose tolerance tests in obese man. Fibrinolysis 1993; 7: 225-228
• 37 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
• 38 Gough SC L, Grant PJ. The fibrinolytic system in diabetes mellitus. Diabet Med 1991; 8: 898-905
• 39 Kruithof EK O. Plasminogen activator inhibitor antigen. In ECAT assay procedures A manual of laboratory techniques. Jespersen J, Bertina RM, Haverkate F. eds Kluwer Academic Publishers; AA Dordrecht, Netherlands: 1992. ppl 51-53
• 40 Panahloo A, Mohamed-Ali V, Lane A, Green F, Humphries S, Yudkin J. Determinants of plasminogen activator inhibitor 1 activity in treated NIDDM and its relation to a polymorphism in the plasminogen activator inhibitor 1 gene. Diabetes 1995; 44: 37-42
• 41 Eriksson P, Kallin B, van’t Hooft F, Bavenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851-1855