Download PDF
Thromb Haemost 1997; 77(02): 357-361
DOI: 10.1055/s-0038-1655968
Original Article
Schattauer GmbH Stuttgart

PAI-1 Concentrations in First-degree Relatives of Patients with Non-insulin-dependent Diabetes: Metabolic and Genetic Associations

Michael W Mansfield
Unit of Molecular Vascular Medicine, Research School of Medicine, University of Leeds, UK
,
Max H Stickland
Unit of Molecular Vascular Medicine, Research School of Medicine, University of Leeds, UK
,
Peter J Grant
Unit of Molecular Vascular Medicine, Research School of Medicine, University of Leeds, UK
› Author Affiliations
Further Information

Publication History

Received 16 July 1996

Accepted after revision 15 October 1996

Publication Date:
10 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

Aim: To identify whether levels of PAI-1 are elevated in relatives of NIDDM patients and the extent to which they relate to features of insulin resistance and to genotype at a common PAI-1 promoter polymorphism.

Results: In 132 first-degree relatives of NIDDM patients and 151 controls PAI-1 activity was higher in relatives 14.4 U/ml than controls U/ml (p <0.0005) with higher body mass index 27.3 v. 24.7 kg/m2 p <0.0005, fasting insulin 9.3 v. 7.6 mU/l p <0.005 and triglyceride v. 1.2 mmol/1 p <0.05. PAI-1 activity levels were higher in men and in smokers and showed a trend to being higher with increasing number of 4G alleles at the PAI-1 promoter polymorphism. After adjustment for age, sex, smoking, BMI and triglyceride levels, PAI-1 levels remained 26% higher in the NIDDM relatives (p = 0.01).

Conclusion: In relatives of NIDDM patients PAI-1 levels are elevated, presenting an additional mechanism for their increased cardiovascular risk.

 

  • References

  • 1 Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR. Role of glucose and insulin resistance in development of type 2 diabetes:results of a 25-year follow-up study. Lancet 1992; 340: 925-929
    CrossrefPubMedSearch in Google Scholar
  • 2 Eriksson J, Fransilla-Kallunki A, Ekstrand A, Saloranta C, Widen E, Schalin C, Groop L. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med 1989; 321: 337-343
    CrossrefPubMedSearch in Google Scholar
  • 3 Stewart MW, Humphriss DB, Berrish TS, Barriocanal LA, Trajano LW, Alberti KGM, Walker M. Features of syndrome X in first-degree relatives of NIDDM patients. Diabetes Care 1995; 18: 1020-1022
    CrossrefPubMedSearch in Google Scholar
  • 4 Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK, Ferrannini E. Parental history of diabetes is associated with increased cardiovascular risk factors. Arteriosclerosis 1989; 09: 928-933
    CrossrefPubMedSearch in Google Scholar
  • 5 Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Increased insulin concentrations in nondiabetic offspring of diabetic patients. N Engl JMed 1988; 319: 1297-1301
    CrossrefPubMedSearch in Google Scholar
  • 6 Kró lewskiAS, Czyzyk A, Kopczynski J, Rywik S. Prevalence of diabetes mellitus, coronary heart disease and hypertension in the families of insulin dependent and insulin independent diabetes. Diabetologia 1981; 21: 520-524
    PubMedSearch in Google Scholar
  • 7 Potter vanLoon BJ, Kluft K, 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
    CrossrefPubMedSearch in Google Scholar
  • 8 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
    CrossrefPubMedSearch in Google Scholar
  • 9 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
    CrossrefPubMedSearch in Google Scholar
  • 10 Juhan-Vague I, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis. Diabetologia 1991; 34: 457-462
    CrossrefPubMedSearch in Google Scholar
  • 11 Hamsten A, de FaireU, Walldius G, Dahlén G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma:Risk for recurrent myocardial infarction. Lancet 1987; 02: 03-09
    PubMedSearch in Google Scholar
  • 12 ECAT Angina Pectoris Study Group. ECAT angina pectoris study:baseline associations of haemostatic factors with extent of coronary arteriosclerosis and other coronary risk factors in 3000 patients with angina pectoris undergoing coronary angiography. Eur Heart J 1993; 14: 08-17
    PubMed
  • 13 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 (PAM) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993; 268: 10739-10745
    PubMedSearch in Google Scholar
  • 14 Eriksson P, Kallin B, van’t HooftFM, 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 SciUSA 1995; 92: 1851-1855
    CrossrefPubMedSearch in Google Scholar
  • 15 Ye S, Green FR, Scarabin PY, Nicaud V, Bara L, Dawson SJ, Humphries SE, Evans A, Luc G, Cambou JP, Arveiler D, Henney AM, Cambien F. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Thromb Haemost 1995; 74: 837-841
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Panahloo A, Mohamed-Ali V, Lane A, Green F, Humphries SE, Yudkin JS. 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
    CrossrefPubMedSearch in Google Scholar
  • 17 Mansfield MW, Heywood DM, Grant PJ. Circulating levels of factor VII, fibrinogen and von Willebrand factor and features of insulin resistance in first-degree relatives of patients with NIDDM. Circulation 1996; 94: 2171-2176
    CrossrefPubMedSearch in Google Scholar
  • 18 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment:insulin resistance and b-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419
    CrossrefPubMedSearch in Google Scholar
  • 19 Mansfield MW, Stickland MH, Grant PJ. Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor-1 in Caucasian patients with non-insulin-dependent diabetes mellitus. Thromb Haemost 1995; 74: 842-847
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 Medvešcek M, Keber D, Stegnar M. Impaired fibrinolysis in offspring of parental pairs with type 2 diabetes mellitus. Diabetologia 1995; 38 (Suppl. 01) A52
    PubMedSearch in Google Scholar
  • 21 Nyholm B, Mengel A, Nielsen S, Moller N, Schimtz O. The insulin resistance in relatives of type 2 diabetic subjects is significantly related to a reduced V02max. Diabetolgia 1994; 37 (Suppl. 01) A28
    PubMedSearch in Google Scholar
  • 22 Schneiderman J, Sawdey MS, Keeton MR, Bordin GM, Bernstein EF, Dilley RB, Loskutoff DJ. Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci USA 1992; 89: 6998-7002
    CrossrefPubMedSearch in Google Scholar
  • 23 Mansfield MW, Stickland MH, Grant PJ. Plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism and coronary artery disease in non-insulin-dependent diabetes. Thromb Haemost 1995; 74: 1032-1034
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Ossei-Gerning N, Mansfield MW, Stickland MH, Wilson IJ, Grant PJ. Plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G genotype and levels in relation to a history of myocardial infarction in patients characterised by coronary angiography. Arterioscler Thromb Vasc Biol. 1997 In Press
    PubMedSearch in Google Scholar
  • 25 Eliasson M, Evrin PE, Lundblad D, Asplund K, Rånby M. Influence of gender, age and sampling time on plasma fibrinolytic variables and fibrinogen. Fibrinolysis 1993; 07: 316-323
    PubMedSearch in Google Scholar
  • 26 Rånby M, Sundell IB, Johnson O, Ledin M-C, Dahlen G. Activity of plasminogen activator inhibitor-1 (PAI-1) in a population in Northern Sweden. Fibrinolysis 1990; 04 (Suppl. 02) 54-55
    PubMedSearch in Google Scholar
  • 27 Mansfield MW, Heywood DM, Grant PJ. Sex differences in coagulation and fibrinolysis in white subjects with non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol 1996; 16: 160-164
    CrossrefPubMedSearch in Google Scholar
  • 28 Faccini FS, Hollenbeck CB, Jeppesen J, Chen YD, Reaven GM. Insulin resistance and cigarette smoking. Lancet 1992; 339: 1128-1130
    CrossrefPubMedSearch in Google Scholar
  • 29 Eliasson B, Attvall S, Taskinen M-R, Smith U. The insulin resistance syndrome in smokers is related to smoking habits. Arterioscler Thromb 1994; 14: 1946-1950
    CrossrefPubMedSearch in Google Scholar
  • 30 Eliasson B, Taskinen MR, Smith U. Long-term use of nicotine gum is associated with hyperinsulinaemia and insulin resistance. Circulation 1996; 94: 878-881
    CrossrefPubMedSearch in Google Scholar