Metformin Decreases the High Plasminogen Activator Inhibition Capacity, Plasma Insulin and Triglyceride Levels in Non-Diabetic Obese Subjects

Summary

We have previously observed a positive correlation between Plasminogen Activator Inhibition capacity (PA Inhibition), Body Mass Index (BMI) and plasma insulin levels in a population of non diabetic subjects. The anti diabetic biguanide Metformin which decreases insulin resistance has been reported to increase the blood fibrinolytic activity. Therefore we have studied the effect of Metformin on PA Inhibition levels in obese subjects with normal glucose tolerance. Eighteen obese women (O) (BMI: 31.4 ± 1.13, m ± S.E.M.) were compared to age matched controls (C) (BMI: 20.2 ± 0.8) and randomized to a 15 days treatment by Metformin (M) (1.7 g/day) or placebo (P) in a double blind study while on a weight maintaining diet. O compared to C had higher levels (m ± S.E.M.) of PA Inhibition (9 ± 1.8 IU/ml, versus 2.88 ± 0.29 p <0.01), lower euglobulin fibrinolytic activity (EFA) (4.95 ±1.17 mm versus 9 ± 0.29 p <0.05), higher plasma insulin (24.1 ±2.1. uU/ml), versus 12 ± 1 p <0.01) and triglyceride (1.32 ± 0.16 mmol/1, versus 0.8 ± 0.08 p <0.05). After 15 days of treatment, in group M a significant decrease in PA Inhibition (5.51 ± 1.4, versus 9.48 ±2.1 p <0.05) in plasma insulin (18.5 ±0.1, versus 24.5 ± 3.5, p <0.05) and plasma triglyceride (1.08 ± 0.1, versus 1.47 ± 0.3 p <0.05) and an increase in EFA (6.50 ± 0.28, versus 5.25 ± 0.35 p <0.05) were observed. No significant variation was observed in group P.

Keywords

Fibrinolysis - Obesity - Metformin - Plasminogen activator inhibition

• References

• 1 Shaw DA, Naughton D. Relationship between blood fibrinolytic activity and body fatness. Lancet 1963; 1: 352-354
• 2 Chakrabarti R, Hocking ED, Fearnley GR. Fibrinolytic effect of metformin in coronary artery disease. Lancet 1965; 2: 256-259
• 3 Vague Ph, Juhan-Vague I, Aillaud MF, Badier C, Viard R, Alessi C, 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; 2: 250-253
• 4 Bagdade J, Bierman EL, Porte D. The significance of basal insulin levels in the evolution of insulin response to glucose in diabetic and non diabetic subjects. J Clin Invest 1967; 46: 1549-1544
• 5 Vague Ph. Effect d’une dose unique de Metformin sur la tolérance au glucose des sujets normaux ou obèses. Le Diabete 1970; 18: 35-39
• 6 National diabetes data group Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979; 28: 1038-1057
• 7 Kluft C, Brakman P, Veldbuyzen-Stolk EC. Screening of fibrinolytic activity in plasma euglobulin fraction on the fibrin plate. In Progress in chemical fibrinolysis and thrombolysis. Davidson JF, Samama MM, Desnoyer PC. (eds.), pp 57-65 Raven Press; New York: 1967
• 8 Juhan-Vague I, Moerman B, De Cock F, Aillaud MF, Collen D. Plasma levels of specific inhibitor of tissue-type plasminogen activator (and urokinase) in normal and pathological conditions. Thromb Res 1984; 33: 523-530
• 9 Gaffney PJ, Curtis AD. A collaborative study of a proposed International Standard for Tissue Plasminogen Activator (t-PA). Thromb Haemostsas 1985; 53: 134-136
• 10 Bucolo G, David M. Quantitative determination of serum triglyceride by use of enzymes. Clin Chem 1973; 19: 475-482
• 11 Fearnley GR, Chakrabarti R, Avis P RD. Blood fibrinolytic activity in diabetes mellitus and its bearing on ischemic heart disease and obesity. Br Med J 1963; 1: 921-923
• 12 Ogston DM, Andrew GM. Fibrinolysis in obesity. Lancet 1964; 2: 1205-1207
• 13 Grace CS, Goldrick RB. Fibrinolysis and body build. Interelationships between blood fibrinolysis. Body composition and parameters of lipid and carbohydrate metabolism. J Atheroscl Res 1968; 8: 705-719
• 14 Warlow CP, McNeill A, Ogston D, Douglas AS. Platelet adhesiveness, coagulation and fibrinolytic activity in obesity. J Clin Pathol 1972; 25: 484-486
• 15 Almer LO, Janzon L. Low fibrinolytic activity in obesity. Thromb Res 1975; 6: 171-175
• 16 Yalow RS, Glick SM, Roth J, Berson SA. Plasma insulin and growth hormone levels in obesity and diabetes. Ann NY Acad Sci 1965; 131: 357-373
• 17 Coccheri S, Cacciari E, Fortunato G, Bergamaschi R, Balsamo A, Lipollani F, Poggi M. Fibrinolytic response to venous occlusion and other haemostatic studies in obese children. Progress in fibrinolysis. Davidson JF, Nilsson IM, Astedt B. (eds.). pp 347-350 Churchill Livingstone; Edinburgh - London - Melbourne - New York: 1981
• 18 Rizkalla SW, Elgrably F, Tchobroutsky G, Slama G. Effect of Metformin treatment of erythrocyte insulin binding in normal weight subjects, in obese non diabetic subjects in type I and type II diabetic patients. Diabète et Métabol 1986; 12: 219-224
• 19 Lord JM, White SI, Bailay CJ, Atkins TW, Fletcher RF, Taylor KG. Effect of Metformin on insulin receptor binding and glycaemic control in type II diabetes. British Medical Journal 1983; 286: 830-831
• 20 Gustafson A, Bjorntorp P, Fahlen M. Metformin administration in hyperlipidaemic states. Acta Med Scand 1971; 190: 421-424
• 21 Sirtori ER, Tremoli E, Sirtori M, Conti F, Paoletti R. Treatment of hypertriglyceridaemia with Metformin. Atheroscler 1977; 26: 583-592
• 22 Goldberg RB. Lipid disorders in diabetes. Diabetes Care 1981; 4: 561-572
• 23 Hocking ED, Chakrabarti JE, Fearnley GR. Effect of biguanides and atromid on fibrinolysis. J Atheroscl Res 1967; 7: 121-130
• 24 Hamsten A, Wiman B, De Faire U, Blombàck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. New Eng J Med 1985; 313: 1557-1563
• 25 Ahmad M, Saku K, Glas-Greenwalt P, Kashyap ML. Inhibitor and activator of plasminogen in patients with hyperlipoproteinemias. Thromb Haemostas 1985; 54: 266 (Abstr n° 158)
• 26 Haglund O, Wibell L, Saldeen T. Plasminogen activators and inhibitors of the plasminogen activators in patients with deep venous thrombosis. Diurnal variation of the inhibitor. Thromb Haemostas 1985; 54: 270 (Abstr n° 1604)
• 27 Juhan-Vague I, Valadier J, Alessi MC, Aillaud MF, Ansaldi J, Philip-Joet C, Holvoet P, Serradimigni A, Collen D. Deficient t-PA release and elevated PA Inhibitor levels in patients with spontaneous or recurrent deep venous thrombosis. Thromb Haemostas 1987; 57: 67-72
• 28 Ducimetiere P, Eschwege E, Richard J, Rosselin G, Claude JR. Clinical complications of coronary heart disease according to plasma insulin and glucose levels. A further analysis of the Paris prospective study. In Advance in Diabetes Epidemiology. Eschwege E. (eds.) Elsevier Biochemical Press; Amsterdam: 1982: 149-155
• 29 Duguid JB. Thrombosis as a factor in the pathogenesis of coronary atherosclerosis. J Pathol 1946; 58: 207-212
• 30 Chakrabarti R, Fearnley GR, Hocking ED, Deliheo SA, Clarke G. Fibrinolytic activity related to age in survivors of myocardial infarction. Lancet 1966; 1: 573-574
• 31 Rosing DR, Redwood DR, Brakman P, Astrup B. Impairment of the diurnal fibrinolytic response in man. Effects of aging, type IV hyperlipoproteinaemia, and coronary artery disease. Circ Res 1973; 32: 752-758
• 32 Peabody RA, Tsapogas MJ, Wu KT. Altered endogenous fibrinolysis and biochemical factors in atherosclerosis. Arch Surg 1974; 109: 309-313
• 33 Pilgeram LO. Abnormalities in clotting and thrombolysis as a risk factor for stroke. Thromb Haemostas 1974; 31: 245-264
• 34 Bouisson H, Thiers JC, Douste-Blazy L, Pieraggi MT, Julian M. Chronic lathyrism and atheromatosis in the rat. Protective effect of Metformin Gerontology 1980; 26: 188-199