Plasminogen Activator Inhibitor (PAI-1) and Non-insulin-dependent Diabetes in Pima Indians, South Asians and Europeans

D K Nagi; W C Knowler; R L Hanson; V Mohamed Ali; J S Yudkin

doi:10.1055/s-0038-1650395

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1996; 75(06): 921-927
DOI: 10.1055/s-0038-1650395

Original Article

Schattauer GmbH Stuttgart

Plasminogen Activator Inhibitor (PAI-1) and Non-insulin-dependent Diabetes in Pima Indians, South Asians and Europeans

Populations at Varying Risk of NIDDM and Coronary Artery Disease

Authors

D K Nagi

¹The Diabetes and Arthritis Epidemiology Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA
W C Knowler

¹The Diabetes and Arthritis Epidemiology Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA
R L Hanson

¹The Diabetes and Arthritis Epidemiology Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA
V Mohamed Ali

²The Department of Medicine, University College London Medical School, London, UK
J S Yudkin

²The Department of Medicine, University College London Medical School, London, UK

Abstract

PDF Download

Summary

Activity of plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of fibrinolysis, is raised in non-insulin-dependent diabetes mellitus (NIDDM) and may contribute to excess macrovascular disease. We investigated the association of PAI-1 activity with NIDDM in Pima Indians, a racial group with low risk of coronary artery disease, but in whom the impact of NIDDM on the occurrence of coronary artery disease is similar to other racial groups. We studied 308 (136 nondiabetic, 172 diabetic) Pima Indians from Arizona, and 138 (98 nondiabetic, 40 diabetic) South Asians and 129 (80 non-diabetic, 49 diabetic) Europeans living in North London. PAI-1 activity was measured by a spectrophotometric assay, and insulin, intact proinsulin and des 31,32 proinsulin concentrations were measured employing highly specific monoclonal antibody-based assays. Compared with non-diabetic subjects, PAI-1 activity was significantly higher in subjects with NIDDM among South Asians (22.8 ± 7.3 vs. 17.4 ± 6.9 AU/ml, p <0.001) and Europeans (23.1 ± 6.6 vs. 16.5 ± 6.1 AU/ml, p <0.001) but not among Pima Indians (19.5 ± 9.6 vs. 18.5 ± 8.6 AU/ml, ns). The association of PAI-1 activity with diabetes remained statistically significant when controlled for age, sex, body mass index and waist-hip ratio, serum triglyceride and fasting insulin concentrations in South Asians (p <0.001) and Europeans (p <0.001). The relationships of PAI-1 activity with clinical and biochemical variables were similar in the three racial groups other than for fasting and 2 h plasma glucose concentrations which were significantly associated with PAI-1 activity in South Asians (partial r = 0.32 and 0.31) and Europeans (partial r = 0.44 and 0.50) but not in Pima Indians (partial r = 0.11 and 0.15). In Pima Indians with NIDDM, PAI-1 activity was similar in those treated with sulphonylureas, insulin, or no drugs for diabetes. In conclusion, the association of PAI-1 with diabetes differs in racial groups who are at different risk of NIDDM and ischaemic heart disease. Previously reported differences in the prevalence of ischaemic heart disease between diabetic and non-diabetic Pima Indians, and between non-diabetic subjects from the three racial groups, are unlikely to be due to differences in PAI-1 activity.

PDF (406 kb)

References

References
1 Wiman B, Hamsten A. The fibrinolytic enzyme system and its role in the etiology of thromboembolic disease. Semin Thromb Haemost 1990; 26: 207-216
2 Auwerx J, Bouillon R, Collen D, Geboers D. Tissue-type plasminogen activator antigen and plasminogen activator inhibitor in diabetes mellitus. Arteriosclerosis 1988; 8: 68-72
3 Garcia FradeLJ, de la Calle H, Torrado MC, Lara JI, Cuellar L, Garcia A. Hypofibrinolysis associated with vasculopathy in non-insulin dependent diabetes mellitus. Thromb Res 1990; 59: 51-59
4 Nagi DK, Jain S, Garvey S, Walji S, Yudkin JS. Defective fibrinolysis in non-insulin-dependent diabetes mellitus relates to plasma insulin concentrations. Clin Sci 1991; 80 (Suppl. 24) 25
5 Juhan VagueI, Roul C, Alessi MC, Ardissone JP, Heim M, Vague P. Increased plasminogen activator inhibitor activity in non-insulin dependent diabetic subjects. Relationship with plasma insulin. Thromb Haemost 1989; 61: 370-373
6 Vague P, Juhan-Vague I, Chabret V, Alessi MC, Atlan C. Fat distribution and plasminogen activator inhibitor activity in nondiabetic obese women. Metabolism 1989; 38: 913-915
7 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
8 Mehta J, Mehta P, Lawson D, Saldeen T. Plasma tissue plasminogen activator inhibitor levels in coronary artery disease: correlation with age and serum triglyceride concentration. J Am Coll Cardiol 1987; 9: 263-268
9 Paramo JA, Colucci M, Collen D, van de Werf F. Plasminogen activator inhibitor in the blood of patients with coronary artery disease. Br Med J 1985; 291: 575-576
10 Hamsten A, Wiman D, de Faire 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
11 Juhan VagueI, Alessi MC, Joly P, Thirion W, Vague P, Declerk PJ, Serra-dimigni A, Collen D. Plasma plasminogen activator inhibitor in angina pectoris. Influence of plasma insulin and acute phase response. Arteriosclerosis 1989; 9: 362-367
12 Hamsten A, Walldius G, Szamosi A, de Faire U, Dahlen G, Landou C, Wiman B, Blombäck M. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; ii: 3-8
13 Gray R, Yudkin JS, Patterson D. Plasminogen activator inhibitor: a risk factor for acute myocardial infarction in diabetic patients. Br Heart J 1993; 69: 228-232
14 Potter van LoonBJ, Kluft C, Radder MA, Blankenstein MA, Meinders AE. The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance. Metabolism 1993; 42: 945-949
15 Juhan VagueI, Thompson SG, Jespersen J. on behalf of the ECAT Angina Pectoris Study Group. Involvement of the haemostatic system in the insulin resistance syndrome. A study of 1500 patients with angina pectoris. Arterioscler Thromb 1993; 13: 1865-1873
16 Juhan VagueI, Vague Ph, Alessi MC, Badier C, Valadier J, Aillaud MF, Atlan C. Relationship between plasma insulin, triglyceride, body mass index, and plasminogen activator inhibitor-1. Diab Metab 1987; 13: 331-336
17 Juhan VagueI, Alessi MC, Vague P. Increased plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and athero-thrombosis. Diabetologia 1991; 34: 457-462
18 Knowler WC, Bennett PH, Hamman RF, Miller M. Diabetes incidence and prevalence in Pima Indians: a 19 fold greater incidence than in Rochester, Minnesota. Am J Epidemiol 1978; 108: 497-505
19 Mather HM, Keen H. The Southall diabetic survey: prevalence of known diabetes in Asians and Europeans. Br Med J 1985; 291: 1081-1084
20 Mohan V, Sharp PS, Cloke HR, Burrin JM, Schumer B, Kohner EM. Serum immunoreactive insulin responses to a glucose load in Asian, Indian and European Type 2 (non-insulin-dependent) diabetic patients and control subjects. Diabetologia 1986; 29: 235-237
21 Sharp PS, Mohan V, Levy JC, Mather HM, Kohner EM. Insulin resistance in patients of Asian, Indian and European origin with non-insulin-dependent diabetes. Horm Metab Res 1987; 19: 84-85
22 McKeigue PM, Marmot MG, Syndercombe CourtYD, Cottier DE, Rahman S, Riemersma RA. Diabetes, hyperinsulinaemia, and coronary risk factors in Bangladeshis in East London. Br Heart J 1988; 60: 390-396
23 Nagulesparan M, Savage PJ, Knowler WC, Johnson GC, Bennett PH. Increased in vivo insulin resistance in non-diabetic Pima Indians compared with Caucasians. Diabetes 1982; 31: 952-956
24 Lillioja S, Nyomba BL, Saad MF, Ferraro R, Castillo C, Bennett PH, Bogardus C. Exaggerated early insulin release and insulin resistance in a diabetes-prone population: a metabolic comparison of Pima Indians and Caucasians. J Clin Endocrinol Metab 1991; 73: 866-876
25 Nelson RG, Sievers ML, Knowler WC, Swinbum BA, Pettitt DJ, Saad FM, Leibow IW, Howard BV, Bennett PH. Low incidence of fatal coronary heart disease in Pima Indians despite high prevalence of non-insulin-dependent diabetes. Circulation 1990; 81: 987-995
26 Sievers ML. Myocardial infarction among southwestern American Indians. Ann Intern Med 1967; 67: 800-807
27 Ingelfinger JA, Bennett PH, Liebow IM, Miller M. Coronary heart disease in the Pima Indians: Electrocardiographic findings and postmortem evidence of myocardial infarction in a population with a high prevalence of diabetes mellitus. Diabetes 1976; 25: 561-565
28 Howard BV, Lisse JR, Knowler WC, Davis MP, Pettitt DJ, Bennett PH. Diabetes and atherosclerosis in the Pima Indians. Mt Sinai J Med (NY) 1982; 49: 169-175
29 Marmot M, Adelstein A. Immigrant mortality in England and Wales 1970-1978. Population Trends 1985; 33: 14-17
30 Nagi DK, Mohamed AliV, Jain SK, Walji S, Yudkin JS. Plasminogen activator inhibitor (PAI-1) activity is elevated in Asian and Caucasian subjects with non-insulin-dependent (type 2) diabetes but not in those with impaired glucose tolerance or non-diabetic Asians. Diab Med 1996; 13: 59-64
31 World Health Organisation. Diabetes mellitus: Report of a WHO Study Group. Technical Report Series No 727, WHO Geneva: 1985
32 Stein MW. D Glucose determination with Hexokinase and Glucose-6-phos-phatase Dehydrogenase. In: Methods of enzymatic analysis Bergmeyer HU. ed Academic Press; New York: 1953: 117
33 Sobey WJ, Beer SF, Carrington CA, Clark PMS, Frank BH, Gray P, Luzio S, Owens DR, Schneider AE, Siddle K, Temple RC, Hales CN. Sensitive and specific two-site immunoradiometric assays to human insulin, proinsulin, 65-66 split and 32-33 split proinsulin. Biochem J 1989; 260: 535-541
34 Mohamed-Ali V, Yudkin JS. An end-point amplified immunoenzymomet-ric assay (IEMA) specific for human insulin. Clin Sci 1992; 82 (Suppl. 27) 4P
35 Mohamed-Ali V, Yudkin JS. Simple and highly sensitive microplate assays (IRMAs) for intact proinsulin and des 31,32 proinsulin. Diabetic Med 1993; 10 (Suppl. 01) 67
36 Chmielewska J, Ranby M, Wiman B. Evidence of a rapid inhibitor to tissue plasminogen activators in plasma. Thromb Res 1983; 31: 427-436
37 Thompson SG, Kienast J, Pyke S, Haverkate F, van de Loo JCW. Haemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Eng J Med 1995; 332: 635-641
38 Dawson S, Hamsten A, Wiman B, Henny A, Humphries S. Genetic variation at the plasminogen activator inhibitor-1 locus is assoicated with altered levels of plasminogen activator inhibitor-1 activity. Arteriosclerosis and Thrombosis 1991; 11: 183-190
39 Panahloo A, Mohamed-Ali V, Lane A, Green F, Humphries S, Yudkin JS. Polymorphism in the promoter of the plasminogen activator (PAI-1) gene as a strong determinant of PAI-1 activity in non-insulin-dependent diabetes. Diabetes 1995; 44: 37-42
40 Bahru Y, Kesteven P, Alberti KG, Walker M. Decreased plasminogen activator inhibitor-1 activity in newly diagnosed type 2 diabetic patients following dietary modification. Diabetic Med 1993; 10: 802-806
41 Jain SK, Nagi DK, Slavin BM, Lumb PJ, Yudkin JS. Insulin therapy in type 2 diabetic subjects suppresses plasminogen activator inhibitor (PAI-1) activity and proinsulin-like molecules independently of glycaemia. Diabetic Med 1993; 10: 27-32
42 Lillioja S, Mott D, Spraul M, Ferraro R, Foley J, Ravussin E, Knowler WC, Bennett PH, Bogardus C. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med 1993; 329: 1988-1992