Effects of Metformin and Metoprolol CR on Hormones and Fibrinolytic Variables during a Hyperinsulinemic, Euglycemic Clamp in Man

Summary

The aim of this study was to characterize the acute effect of euglycemic (glucose 5.2 ± 0.6 mrnol/1) hyperinsulinemia (mean 118 ± 32 mU/1) on fibrinolytic variables, free fatty acids (FFA) and counter-regulatory hormones. In addition, the effect of chronic treatment with metformin, an oral antidiabetic agent which enhances insulin action, and metoprolol CR, a relatively betaj-selective adrenergic antagonist, was also evaluated. A randomized, double-blind, placebo-controlled, cross-over study including 18 non-obese men, aged 53 ± 6 years, was performed. The investigations were performed after each treatment period of 6 weeks in both the postabsorptive state and during a euglycemic, hyperinsulinemic clamp.

Compared to the postabsorptive state, plasminogen activator inhibitor (PAI-1) activity and antigen, tissue plasminogen activator (t-PA) antigen and FFA decreased (p <0.001) after 120 min of euglycemic hyperinsulinemia. In addition, t-PA activity increased (p <0.01) while blood levels of lipoprotein (a), catecholamines and cortisol remained unchanged. Growth hormone increased during the clamps and this was most pronounced after treatment with metoprolol CR.

When the effect of treatment was compared, postabsorptive levels of C-peptide, FFA and t-PA antigen were lower after metformin than after the placebo period (p <0.05). t-PA antigen also remained lower during the clamp after metformin treatment. No significant effects of metformin or metoprolol CR were seen on insulin-stimulated glucose uptake during the clamps or on postabsorptive levels of counterregulatory hormones, PAI-1 or Lp(a).

Thus, the rapidly increased fibrinolytic activity after 2 h hyperinsulinemia with maintained euglycemia can not be explained by the concomitant changes in counterregulatory hormones. It is more likely that the decreased FFA and/or triglyceride levels play a role.

• References

• 1 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
• 2 Kluft C, Jie AFH, Rijken DC, Verheijen JH. Daytime fluctuations in blood of tissue-type plasminogen activator (t-PA) and its fast-acting inhibitor (PAI-1). Thromb Haemost 1988; 59: 329-32
• 3 Rizza R, Cryer PE, Gerich JE. Role of glucagon, catecholamines, and growth hormone in human glucose counteraction. J Clin Invest 1979; 64: 62-71
• 4 Lager I, Attvall S, Eriksson BM, von Schenck H, Smith U. Studies on the insulin-antagonistic effect of catecholamines in normal man. Evidence for the importance of (β₂-receptors. Diabetologia 1986; 29: 409-16
• 5 Teger-Nilsson AC, Dahlöf C, Haglund E, Hedman C, Olsson G, Åblad B. Influence of metoprolol CR/ZOC on plasminogen activator inhibitor (PAI-1) in man. A pilot study. J Clin Pharmacol 1990; 30: S132-7
• 6 Sparre Hermann L, Melander A Biguanide. Basic aspects and clinical uses. In: International Textbook of Diabetes Mellitus Alberti KGMM, DeFronzo RA, Keen H, Zimmet P. eds John Wiley & Sons Ltd; 1992. pp 773-95
• 7 Vague P, Juhan-Vague I, Alessi MC, Badier C, Valadier J. Metformin decreases the high plasminogen activator inhibition capacity, plasma insulin and triglyceride levels in non-diabetic obese subjects. Thromb Haemost 1987; 57: 326-8
• 8 Grant PJ, Stickland MH, Booth NA, Prentice CRM. Metformin causes a reduction in basal and post-venous occlusion plasminogen activator inhibitor-1 in type 2 diabetic patients. Diab Med 1991; 8: 361-5
• 9 Landin K, Tengborn L, Smith U. Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors. J Intern Med 1991; 229: 181-7
• 10 Landin K, Tengborn 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: 273-8
• 11 Stiko-Rahm A, Wiman B, Hamsten A, Nilsson J. Secretion of plasminogen activator inhibitor-1 from cultured human umbilical vein endothelial cells induced by very low density lipoprotein. Arteriosclerosis 1990; 10: 1067-73
• 12 Edén S, Wiklund O, Oscarsson J, Rosén T, Bengtsson BÅ. Growth hormone treatment of growth hormone deficient adults results in a marked increase in Lp(a) and HDL cholesterol concentrations. Arterioscler Thromb 1993; 13: 296-301
• 13 DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237: E214-223
• 14 Landin K, Lönnroth P, Krotkiewski M, Holm G, Smith U. Increased insulin resistance and fat cell lipolysis in obese but not lean women with a high waist/hip ratio. Eur J Clin Invest 1990; 20: 530-5
• 15 Grant PJ, Kruithof KO, 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 Science 1990; 79: 513-6
• 16 Fearney GR, Vincent CT, Chakrabarti R. Reduction of blood fibrinolytic activity in diabetes mellitus by insulin. Lancet 1959; 2: 1067
• 17 Jem C, Eriksson E, Tengborn L, Risberg B, Wadenvik H, Jern S. Changes of plasma coagulation and fibrinolysis in response to mental stress. Thromb Haemost 1989; 62: 767-71
• 18 Rowe JW, Young JB, Minaker KL, Stevens AL, Pallotta J, Landsberg L. Effect of insulin and glucose infusions on sympathetic nervous system activity in normal man. Diabetes 1981; 30: 219-25
• 19 Mitrakou A, Mokan M, Bolli G, Veneman T, Jenssen T, Cryer P, Gerich J. Evidence against the hypothesis that hyperinsulinemia increases sympathetic nervous system activity in man. Metabolism 1992; 41: 198-200
• 20 Bolli GB, Gottesman IS, Cryer PE, Gerich JE. Glucose counterregulation during prolonged hypoglycemia in normal humans. Am J Physiol 1984; 247: E206-E214
• 21 Lager I, Jagenburg R, von Schenck H, Smith U. Effect of beta-blockade on hormone release during hypoglycemia in insulin-dependent diabetics. Acta Endocrinol 1980; 95: 365-71
• 22 Rånby M, Bergsdorf N, Nilsson T, Mellbring G, Winblad B, Bucht G. Age dependence of tissue plasminogen activator in plasma, as studied by an improved enzyme-linked immunosorbent assay. Clin Chem 1986; 32: 2160-5
• 23 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
• 24 Kooistra T, Bosma PJ, Tons HAM, van den Berg AP, Meyer P, Princen MG. Plasminogen activator inhibitor-1: biosynthesis and mRNA level are increased by insulin in cultured human hepatocytes. Thromb Haemost 1989; 62: 723-8
• 25 Mussoni L, Mannucci L, Sirtori M, Camera M, Maderna P, Sironi L, Tremoli E. Hypertriglyceridemia and regulation of fibrinolytic activity. Arterioscler Thromb 1992; 12: 19-27
• 26 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