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Thromb Haemost 1994; 71(06): 731-736
DOI: 10.1055/s-0038-1642514
Review Article
Schattauer GmbH Stuttgart

Polymorphisms of the Plasminogen Activator Inhibitor- 1 Gene in Type 1 and Type 2 Diabetes, and in Patients with Diabetic Retinopathy

M W Mansfield
The Diabetes and Thrombosis Research Group, The Divison of Medicine, The School of Medicine, University of Leeds, Leeds General Infirmary, Leeds, UK
,
M H Stickland
The Diabetes and Thrombosis Research Group, The Divison of Medicine, The School of Medicine, University of Leeds, Leeds General Infirmary, Leeds, UK
,
A M Carter
The Diabetes and Thrombosis Research Group, The Divison of Medicine, The School of Medicine, University of Leeds, Leeds General Infirmary, Leeds, UK
,
P J Grant
The Diabetes and Thrombosis Research Group, The Divison of Medicine, The School of Medicine, University of Leeds, Leeds General Infirmary, Leeds, UK
› Author Affiliations
Further Information

Publication History

Received: 17 December 1993

Accepted after revision: 23 February 1994

Publication Date:
09 July 2018 (online)

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Summary

To identify whether genotype contributes to the difference in PAI-1 levels in type 1 and type 2 diabetic subjects and whether genotype relates to the development of retinopathy, a Hind III restriction fragment length polymorphism and two dinucleotide repeat polymorphisms were studied. In 519 Caucasian diabetic subjects (192 type 1, 327 type 2) and 123 Caucasian control subjects there were no differences in the frequency of the Hind III restriction alleles (type 1 vs type 2 vs control: allele 1 0.397 vs 0.420 vs 0.448; allele 2 0.603 vs 0.580 vs 0.552) nor in the allelic frequency at either dinucleotide repeat sequence. In 86 subjects with no retinopathy at 15 years or more from diagnosis of diabetes and 190 subjects with diabetic retinopathy there was no difference in the frequency of Hind III restriction alleles (retinopathy present vs retinopathy absent: allele 1 0.400 vs 0.467; allele 2 0.600 vs 0.533) nor in the allelic frequencies at either dinucleotide repeat sequence. The results indicate that there is no or minimal influence of the PAI-1 gene on either PAI-1 levels or the development of diabetic retinopathy in patients with diabetes mellitus.

 

  • References

  • 1 Cash JD, McGill RC. Fibrinolytic response to moderate exercise in young male diabetics and non-diabetics. J Clin Pathol 1969; 22: 32-5
    PubMedGoogle Scholar
  • 2 Sharma SC. Platelet adhesiveness, plasma fibrinogen and fibrinolytic activity in juvenile-onset and maturity-onset diabetes mellitus. J Clin Pathol 1981; 34: 501-3
    CrossrefPubMedGoogle Scholar
  • 3 Nilsson TK, Lithner F. Glycaemic control, smoking habits and diabetes duration affect the extrinsic fibrinolytic system in type 1 diabetic patients but microangiopathy does not. Acta Med Scand 1988; 224: 123-9
    PubMedGoogle Scholar
  • 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: 954-9
    CrossrefPubMedGoogle Scholar
  • 5 Wieczorek I, Pell ACH, Mclver B, Mac Gregor IR, Ludlam CA, Frier BM. Coagulation and fibrinolytic systems in type 1 diabetes: effects of venous occlusion and insulin-induced hypoglycaemia. Clin Sci 1993; 84: 79-86
    CrossrefPubMedGoogle Scholar
  • 6 Vicari AM, Vigano D’Angelo S, Testa S, Comi G, Galardi G, Orsi E, D’Angelo A. Normal tissue plasminogen activator and plasminogen activator inhibitor activity in plasma from patients with type 1 diabetes mellitus. Horn Metab Res 1992; 24: 516-9
    PubMedGoogle Scholar
  • 7 Lee P, Jenkins A, Bourke C, Santamaria J, Paton C, Janus E, Best J. Prothrombotic and antithrombotic factors are elevated in patients with type 1 diabetes complicated by microalbuminuria. Diabet Med 1993; 10: 122-8
    CrossrefPubMedGoogle Scholar
  • 8 Mahmoud R, Raccah MC, Alessi MC, Aillaud MF, Juhan-Vague I, Vague P. Fibrinolysis in insulin dependent patients with or without nephropathy. Fibrinolysis 1992; 6: 105-9
    PubMedGoogle Scholar
  • 9 Ostermann H, Tschope D, Greber W, Meyer-Rlisenberg HW, van de Loo J. Enhancement of spontaneous fibrinolytic activity in diabetic retinopathy. Thromb Haemost 1992; 68: 400-3
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Grant MB, Fitzgerald C, Guay C, Lottenberg R. Fibrinolytic capacity following stimulation with desmopressin acetate in patients with diabetes mellitus. Metabolism 1989; 9: 901-7
    PubMedGoogle Scholar
  • 11 Auwerx J, Bouillon R, Collen D, Geboers J. Tissue-type plasminogen activator antigen and plasminogen activator inhibitor in diabetes mellitus. Arteriosclerosis 1988; 8: 68-72
    CrossrefPubMedGoogle Scholar
  • 12 Haitas B, Barnes AJ, Cederholm-Williams SA, Moore J, Shogry MEC, Turner RC. Abnormal endothelial release of fibrinolytic activity and fibronectin in diabetic microangiopathy. Diabetologia 1984; 27: 493-6
    CrossrefPubMedGoogle Scholar
  • 13 Juhan-Vague I, Vague P, Poisson C, Aillaud MF, Mendez C, Collen D. Effect of 24 hours of normoglycaemia on tissue-type plasminogen activator plasma levels in insulin-dependent diabetes. Thromb Haemost 1984; 51: 97-8
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Fuller JH, Keen H, Jarrett RJ, Omer T, Meade TW, Chakrabarti R, North WRS, Stirling Y. Haemostatic variables associated with diabetes and its complications. BMJ 1979; 2: 964-6
    CrossrefPubMedGoogle Scholar
  • 15 Aimer LO, Nilsson IM. On fibrinolysis in diabetes mellitus. Acta Med Scand 1975; 198: 101-6
    PubMedGoogle Scholar
  • 16 Schneider SH, Kim HC, Khachadurian AK, Ruderman NB. Impaired fibrinolytic response to exercise in type II diabetes: Effects of exercise and physical training. Metabolism 1988; 37: 924-9
    CrossrefPubMedGoogle Scholar
  • 17 García Frade LJ, de la Calle H, Torrado MC, Lara JI, Cuellar L, García Avello A. Hypofibrinolysis associated with vasculopathy in non insulin dependent diabetes mellitus. Thromb Res 1990; 59: 51-9
    CrossrefPubMedGoogle Scholar
  • 18 Gough SCL, Rice PJS, Mc Cormack 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: 638-42
    CrossrefPubMedGoogle Scholar
  • 19 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: 370-3
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Nagi DK, Jain S, Garvey S, Walji S, Yudkin JS. Defective fibrinolysis in non-insulin-dependent diabetes relates to plasma insulin concentrations. Clin Sci 1991; 80 Suppl (Suppl. 24) 25
    CrossrefPubMedGoogle Scholar
  • 21 van Weiscli JWJ, Weslerhuis LWJMM, Venekamp WJRR. Glycometabolic control and fibrinolysis in diabetic patients. Haemostasis 1990; 20: 241-50
    PubMedGoogle Scholar
  • 22 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: 491-4
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Grant PJ, Ruegg M, Medcalf RL. Basal expression and insulin-mediated induction of PAI-1 mRNA in Hep G2 cells. Fibrinolysis 1991; 5: 81-6
    PubMedGoogle Scholar
  • 24 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: 723-8
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Barnett AH, Eff C, Leslie RDG, Pyke DA. Diabetes in identical twins. Diabetologia 1981; 20: 87-93
    CrossrefPubMedGoogle Scholar
  • 26 Rydzewski A, Kawamura H, Watanabe I, Takada Y, Takada A. Plasminogen activators and plasminogen activator inhibitor (PAI-1) in type II diabetes mellitus. Fibrinolysis 1990; 4: 183-8
    PubMedGoogle Scholar
  • 27 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; 11: 183-90
    CrossrefPubMedGoogle Scholar
  • 28 Klinger KW, Winqvist R, Riccio A, Andreasen PA, Sartorio R, Nielsen LS, Stuart N, Stanislovitis P, Watkins P, Douglas R, Grzeschik K-H, Alitalo K, Blasi F, Danø K. Plasminogen activator inhibitor type 1 gene is located at region q21.3-q22 of chromosome 7 and genetically linked with cystic fibrosis. Proc Natl Acad Sci USA 1987; 84: 8548-52
    CrossrefPubMedGoogle Scholar
  • 29 Weber JL, May PA. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet 1989; 44: 388-96
    PubMedGoogle Scholar
  • 30 Leslie RDG, Pyke DA. Diabetic retinopathy in identical twins. Diabetes 1982; 31: 19-21
    CrossrefPubMedGoogle Scholar
  • 31 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: 1009-15
    CrossrefPubMedGoogle Scholar
  • 32 Brownlee M, Vlassara H, Cerami A. Non-enzymatic glycosylation reduces the susceptibility of fibrin to degradation by plasmin. Diabetes 1983; 32: 680-4
    CrossrefPubMedGoogle Scholar
  • 33 Vlassara H, Brownlee M, Manogue KR, Dinarello CA, Pasagian A. Cachectin/TNF and IL-1 induced by glucose modified proteins: Role in normal tissue remodelling. Science 1988; 240: 1546-8
    CrossrefPubMedGoogle Scholar
  • 34 van Hinsberg VWM, Kooistra T, van den Berg EA. et al Tumour necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo. Blood 1988; 72: 1467-73
    PubMedGoogle Scholar
  • 35 Medcalf RL, Kruithof EKO, Schleuning WD. PAI-1 and PAI-2 are TNF/ cachectin-responsive genes. J Exp Med 1988; 168: 751-9
    CrossrefPubMedGoogle Scholar
  • 36 Gunnarsson R, Nyman D, Wålinder O, Östman J. Fibrinolytic activity and diabetes control Evidence for a relationship. A preliminary report. Acta Med Scand Suppl 1980; 639: 23-4
    PubMedGoogle Scholar
  • 37 Juhan-Vague I, Alessi MC, Joly P, Thirion X, 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: 362-7
    CrossrefPubMedGoogle Scholar
  • 38 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: 250-3
    CrossrefPubMedGoogle Scholar
  • 39 Grant PJ, Kruithof EKO, 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: 513-6
    CrossrefPubMedGoogle Scholar
  • 40 Potter van Loon BJ, de Bart ACW, 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; 4 Suppl (Suppl. 02) 93-4
    PubMedGoogle Scholar
  • 41 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: 130-3
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Mc Cormack L, Stickland MH, Grant PJ. Plasminogen activator inhibitor-1 antigen concentrations during insulin and oral glucose tolerance tests in obese man. Fibrinolysis 1993; 7: 225-8
    PubMedGoogle Scholar
  • 43 Juhan-Vague I, Alessi MC. Plasminogen activator inhibitor 1 and atherothrombosis. Thromb Haemost 1993; 70: 138-43
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977-86
    CrossrefPubMedGoogle Scholar
  • 45 Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to inter-leukin-1 in HepG2 cells. J Biol Chem 1993; 268: 10739-15
    CrossrefPubMedGoogle Scholar