Relationships of Insulin and Intact and Split Proinsulin to Haemostatic Function in Young Men with and without Coronary Artery Disease

Summary

Glucose intolerance, hyperinsulinaemia, dyslipoproteinaemia and multiple disturbances of haemostatic function are characteristics of young men with premature coronary artery disease. The relations between glucose, insulin and insulin propeptides, in the fasting state, and after an oral glucose load, and haemostatic function were examined in 62 consecutive non-diabetic men with myocardial infarction before the age of 45 and in 41 age-matched healthy men. “True” hyperinsulinaemia, raised plasma concentrations of insulin propeptides, dyslipoproteinaemia, elevated plasma levels of fibrinogen, factor VII antigen (VIIag) and plasminogen activator inhibitor-1 (PAI-1) activity, and lower antithrombin activity (p <0.05-0.001) characterized the patients. PAI-1 activity was more closely associated with insulin, intact proinsulin and des 31,32proinsulin in patients than in controls, whereas the plasma levels of fibrinogen, activated factor VII (VIIa) and VIIag were stronger correlated with insulin and insulin propeptides in subjects without coronary artery disease. Very low density lipoprotein (VLDL) triglyceride was a strong determinant of VIIag and PAI-1 activity levels in both cases and controls, whereas VLDL triglyceride in controls and LDL cholesterol in patients related significantly to the plasma fibrinogen concentration. Thus, our data suggests that plasma insulin and insulin propeptides might be involved in the regulation of plasma fibrinogen concentration, factor VII level and plasma PAI-1 activity. However, apolipoprotein B-containing lipoproteins appear to influence the relationships between insulin, insulin propeptides and haemostatic factors in individuals with premature coronary artery disease.

• References

• 1 Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H. Coronary heart disease risk and impaired glucose tolerance. The Whitehall Study Lancet 1980; 1: 154-160
• 2 Welborn TA, Wearne K. Coronary heart disease and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care 1979; 2: 154-160
• 3 Ducimetiere D, Eschwege E, Papoz L, Richard JL, Claude JR, Rosselin G. Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia 1980; 19: 205-210
• 4 Pyörölö K, Savolainen S, Kaukola S, Haapakoski J. Plasma insulin as coronary heart disease risk factor: Relationship to other risk factors and predictive value during 9 1/2-year follow-up of the Helsinki policeman study population. Acta Med Scand 1985; 701 Suppl 38-52
• 5 Hamsten A, Wiman B, 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
• 6 Hamsten A, Walldius S, Dahlén G, Johansson B, de FaireU. Serum lipoproteins and apolipoproteins in young male survivors of myocardial infarction. Atherosclerosis 1986; 59: 223-225
• 7 Hamsten A, Blombäck M, Wiman B, Svennsson J, Szamosi A, de Faire U, Mettinger L. Haemostatic function in myocardial infarction. Br Heart J 1986; 55: 58-66
• 8 Hamsten A, Eféndic S, Walldius G, Szamosi A, de FaireU. Glucose tolerance and insulin response to glucose in nondiabetic young male survivors of myocardial infarction. Am Heart J 1987; 113: 917-927
• 9 Hamsten A, de FaireU, Walldius G, Dahlén G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: Risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9
• 10 Modan M, Halkin H, Lusky A, Segal P, Fuchs Z, Chetrit A. Hyper-insulinemia is characterized by jointly disturbed plasma VLDL, LDL and HDL levels. A population-based study Arteriosclerosis 1988; 8: 227-236
• 11 Morales PA, Mitchell BD, Valdez RA, Hazuda HP, Stern MP, Haffner SM. Incidence of NIDDM and impaired glucose tolerance in hypertensive subjects. The San Antonio Heart Study Diabetes 1993; 42: 154-161
• 12 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
• 13 McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes 1994; 43: 104-109
• 14 Potter van LoonB J, 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
• 15 Temple RC, Clark PM, Nagi DK, Schneider AE, Yudkin JS, Hales CN. Radioimmunoassay may overestimate insulin in non-insulin-dependent diabetics. Clin Endocrinol 1990; 32: 689-693
• 16 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
• 17 Kooistra T, Bosma PJ, Töns HA, van derBerg, Meyer P, Princen HM G. Plasminogen activator inhibitor 1 : Biosynthesis and mRNA level are increased by insulin in cultured human hepatocytes. Thromb Haemostas 1989; 62: 723-728
• 18 Schneider DJ, Sobel BE. Augmentation of synthesis of plasminogen activator inhibitor type-1 by insulin and insulin-like growth factor type-1 implications for vascular disease by hyperinsulinemic states. Proc Natl AcadSci 1991; 88: 9959-9963
• 19 Schneider DJ, Nordt TK, Sobel BE. Stimulation by proinsulin of expression of plasminogen activator inhibitor type-1 in endothelial cells. Diabetes 1992; 41: 890-895
• 20 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
• 21 Nagi DK, Hendra TJ, Ryle AJ, Cooper TM, Temple RC, Clark PM, Schneider AE, Hales CN, Yudkin JS. The relationship 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
• 22 Juhan-Vague I, Alessi MC, Joly P, Thirion X, Vague P, Declerck PJ, Serra-dimigni A, Collen D. Plasma plasminogen activator inhibitor-1 in aninga pectoris. Influence of plasma insulin and acute-phase response Arteriosclerosis 1989; 9: 362-367
• 23 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
• 24 Juhan-Vague I, Thompson SG, Jespersen J. On behalf of the ECAT Angina Pectoris Study Group. Involvement of the hemostatic system in the insulin resistance syndrome Arterioscler Thromb 1993; 13: 1865-1873
• 25 Folsom AR, Qamtrieh HT, Wing RR, Jeffrey RW, Stinson VL, Kuller LH, Wu KK. Impact of weight loss on plasminogen activator inhibitor (PAI-1), factor VII, and other haemostatic factors in moderately overweight adults. Arterioscler Thromb 1993; 13: 162-169
• 26 Tornvall P, Båvenholm P, Landou C, de Faire U, Hamsten A. Relation of plasma levels and composition of apolipoprotein B-containing lipoproteins to angiographically-defmed coronary artery disease in young patients with myocardial infarction. Circulation 1993; 88 part (Suppl. 01) 2180-2189
• 27 Vermylen C, de Vreker RA, Verstraete M. A rapid enzymatic method for assay of fibrinogen fibrin polymerization time (FPT). Clin Chim Acta 1963; 8: 418-424
• 28 Wildgoose P, Nemerson Y, Hansen LL, Nielsen EE, Glazer S, Hedner U. Measurement of basal levels of factor VIIa in hemophilia A and B patients. Blood 1992; 80: 25-28
• 29 Morrisey JH, Macik BG, Neuenschwander PF, Comp PC. Quantification of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993; 81: 734-744
• 30 Silveira A, Green F, Karpe F, Blombäck M, Humphries S, Hamsten A. Elevated levels of factor VII activity in the postprandial state: effect of the factor VII Arg-Gln polymorphism. Thromb Haemost 1994; 72: 734-739
• 31 Abildgaard U, Lie M, Odegård OR. Antithrombin (heparin cofactor) assay with “new” chromogenic substrates (S-2238 and Chromozym TH). Thromb Res 1977; 11: 549-553
• 32 Odegaard OR, Try K, Andersson TR. Protein C: An automated activity assay. Haemostasis 1987; 17: 109-113
• 33 Chmielewska J, Rånby M, Wiman B. Evidence for a rapid inhibitor to tissue plasminogen activator in plasma. Thromb Res 1983; 31: 427-436
• 34 Carlsson K. Lipoprotein fractionation. J Clin Pathol 1973; 5 suppl (Suppl. 26) 32-37
• 35 Sobey WJ, Beer SF, Carrington CA, Clark P MS, Frank BH, Gray IP, Luzio SD, Owens DR, Schneider AE, Siddle K, Temple RC, Hales CN. Sensitive and specific two-side immunoradiometric assays for human insulin, proinsulin, 65-66 split and 32-33 split proinsulins. Biochem J 1989; 260: 535-541
• 36 Proudler AJ, Godsland IF, Stevenson JC. Insulin propeptides in conditions associated with insulin resistance in humans and their relevance to insulin measurements. Metabolism 1994; 43: 446-449
• 37 Yang X-C, Jing T-Y, Resnick LM, Phillips GB. Relations of hemostatic factors to other risk factors for coronary heart disease and to sex hormones in men. Arterioscler and Thromb 1993; 13: 467-471
• 38 Phillips GB. Relationship between sex hormones and glucose, insulin, and lipid abnormalities in men with myocardial infarction. Proc Natl Acad Sci USA 1977; 74: 1729-1733
• 39 Phillips GB. Relationship between serum sex hormones and glucoseinsulin-lipid defect in men with obesity. Metabolism 1993; 42: 116-120
• 40 Johansson J-O, Landin K, Tengborn L, Rosen T, Bengtsson B-A. High fibrinogen and plasminogen activator inhibitor activity in growth hormone-deficient adults. Arterioscler Thromb 1994; 14: 434-437
• 41 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
• 42 Padayatty SJ, Orme S, Zenobi PD, Stickland MH, Belchetz PE, Grant PJ. The effects of insulin-like growth factor-1 on plasminogen activator inhibitor-1 synthesis and secretion: results from in vitro and in vivo studies. Thromb Haemost 1993; 70: 1009-1013
• 43 Anfosso F, Chomiki N, Alessi MC, Vague P, Juhan-Vague I. Plasminogen activator inhibitor-1 synthesis in the human hepatoma cell line Hep G2. Metformin inhibits the stimulating effect of insulin J Clin Invest 1993; 91: 2185-2193
• 44 Dawson S, Henney A. The status of PAI-1 as a risk factor for arterial and thrombotic disease. A review Atherosclerosis 1992; 95: 105-117
• 45 Yudkin J. Circulating proinsulinlike molecules. J Diab Comp 1993; 7: 113-123
• 46 Handa K, Kono S, Saku K, Sasaki J, Kawano T, Sasaki I, Hiroki T, Arakawa K. Plasma fibrinogen levels as an independent indicator of severity of coronary atherosclerosis. Atherosclerosis 1989; 77: 209-213
• 47 Broadhurst P, Kelleher C, Hughes L, Imerson JD, Raffery EB. Fibrinogen, factor VII clotting activity and coronary artery disease severity. Atherosclerosis 1990; 85: 169-173
• 48 Peltonen S, Kauhanen M, Lepantalo M, Lassila R. The severity of atherosclerosis is associated with fibrinogen and degradation of cross-linked fibrin. Fibrinolysis 1992; 6: 31-32
• 49 Ernst E, Reschl KL. Fibrinogen as a cardiovascular risk factor: A meta-analysis and review of the literature. Ann Intern Med 1993; 118: 956-963
• 50 Meade TW, Imeson J, Stirling Y. Effects of changes in smoking and other characteristics on clotting factors and the risk of ischaemic heart disease. Lancet 1987; 2: 986-987
• 51 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North W RS, Haines AP, Stirling Y, Imeson J D, Thompson SG. Haemostatic function and ischaemic heart disease: Principal results of the Northwick Park Heart Study. Lancet 1986; 1: 533-537
• 52 Scarabin PY, Bara L, Samama M, Orssaud G. Further evidence that activated factor VII is related to plasma lipids. Br J Haematol 1985; 61: 186-187
• 53 Silveira A, Karpe F, Blombäck M, Steiner G, Walldius G, Hamsten A. Activation of coagulation factor VII during alimentary lipemia. Arterioscler Thromb 1994; 14: 60-69
• 54 Mitropoulus KA, Miller GJ, Watts GF, Durrington PN. Lipolysis of triglyceride-rich lipoproteins activates coagulant factor XII: a study in familial lipoprotein-lipase deficiency. Atherosclerosis 1992; 95: 119-125
• 55 Meade TW, Cooper J, Miller GJ, Howarth DJ, Stirling Y. Antithrombin III and arterial disease. Lancet 1991; 337: 850-851
• 56 Pollare T, Lithell H, Selinus I, Berne C. Sensitivity to insulin during treatment with atenolol and metoprolol: a randomized, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients. Br Med J 1989; 298: 1152-1157
• 57 Andersson P-E, Johansson J, Berne C, Lithell H. Effects of selective alphal and beta 1-adrenoreceptor blockade on lipoprotein and carbohydrate metabolism in hypertensive subjects, with special emphasis on insulin sensitivity. J Human Hypertens 1994; 8: 219-226
• 58 Landin K, Tengborn L, Smith U. Effects of metformin and metoprolol CR on hormones and fibrinolytic variables during a hyperinsulinaemic, euglycaemic clamp in man. Thromb Haemost 1994; 71: 783-787
• 59 Teger-Nilsson AC, Dahlöf C, Haglund E, Hedman C, Olsson G, Åblad B. Influence of metoprolol CR/ZOK on plasminogen activator inhibitor (PAI-1) in man: A pilot study. J Clin Pharmacol 1990; 30: S132-S137
• 60 Teger-Nilsson AC, Larsson T, Hjemdahl P, Olsson G. Fibrinogen and plasminogen activator inhibitor-1 in hypertension and coronary heart disease. Circulation 1991; 84: VI-72-VI-77
• 61 Jansson JH, Johansson B, Boman K, Nilsson TK. Effects of doxazosin and atenolol on the fibrinolytic system in patients with hypertension and elevated serum cholesterol. Eur J Clin Pharmacol 1991; 40: 321-326
• 62 Berglund B, Wallentin L, von SchenkH. Platelets function and plasma fibrinogen and their relations to gender, smoking habits, obesity and β-blocker in young survivors of myocardial infarction. Thromb Haemost 1988; 60: 21-24
• 63 Båvenholm P, Malmberg K, Efendic S, Wiman B, de Faire U, Hamsten A. Hyperinsulinaemia, Hypertriglyceridaemia and impaired fibrinolytic function: concordant abnormalities associated with myocardial infarction at young age. Nutrition, Metabolism, and Cardiovascular Diseases (NMCD) 1993; 3: 28-37