The Effects of Insulin-Like Growth Factor-1 on Plasminogen Activator Inhibitor-1 Synthesis and Secretion: Results from In Vitro and In Vivo Studies

Summary

In vitro studies have shown that insulin and IGF-1 releases the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1) from cells of hepatic origin. To investigate the effects of IGF-1 on fibrinolysis: 1) cultured hepatoma cells were grown in the presence of IGF-1 and media collected for secreted PAI-1 and cells probed for PAI-1 mRNA, 2) 8 hypopituitary patients were treated with recombinant human growth hormone (rhGH) and 3) 5 type 2 diabetic patients were treated with recombinant human IGF-1 (rhIGF-1). Treatment of Hep G2 cells with IGF-1 (1000 ng/ml) increased secretion of PAI-1 from a median value of 80 ng/10⁶ cells (range 21-91) to 144 ng/10⁶ cells (range 128-169) after 24 h (p <0.01). Synthesis of PAI-1 mRNA increased in a similar fashion. Treatment of hypopituitary patients with rhGH led to an increase in circulating IGF-1 from a mean value of 166 (range 41-324) ng/ml at baseline to 322 (77-575) ng/ml at 4 weeks and 259 (104-533) ng/ml after 8 weeks (p <0.02). Despite this, no changes in circulating PAI-1 or fibrinolysis occurred. Type II diabetic patients treated with rhIGF-1 showed an increase in circulating IGF-1 from a mean value of 120 ng/ml (range 109-196), at baseline to 823 ng/ml (585-894) after 5 days. This also was not associated with changes in circulating PAI-1 or in fibrinolysis. The results confirm that IGF-1 induces the synthesis of PAI-1 in Hep G2 cells. However, marked increases in IGF-1 had no effect on circulating PAI-1 or fibrinolysis.

• References

• 1 Rosen T, Bengtsson B-A. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990; 336: 285-288
• 2 Salmon F, Cuneo RC, Hesp R, Sonksen P. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 1989; 321: 1797-1803
• 3 Jorgensen JDL, Thuesen L, Ingemann-Hansen T. et al. Beneficial effects of growth hormone treatment in GH deficient adults. Lancet 1989; i: 1221-1224
• 4 Rudman D, Feller AG, Nagraj HJ. et al. Effects of human growth hormone in men over 60 years old. N Engl J Med 1990; 323: 1-6
• 5 Hamsten A, Wiman B, deFaire U, Blomback 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, Defaire U, Waldius G, Dahlen G, Szamosi A, Landou C. et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; ii: 3-9
• 7 Kooistra T, Bosma PJ, Tons HAM, van den Berg AP, Meyer P, Princen HMG. Plasminogen activator inhibitor 1 :Biosynthesis and mRNA level are increased by insulin in cultured human hepatocytes. Thromb Haemostas 1989; 62: 723-728
• 8 Grant PJ, Ruegg M, Medcalf RL. Basal expression and insulin mediated induction of PAI-1 mRNA in Hep G2 cells. Fibrinolysis 1991; 5: 81-86
• 9 Juhan-Vague I, Vague P, Alessi MC, Badier C, Valadier J, Ailaud MF. Relationships between plasma insulin, triglyceride, body mass index and plasminogen activator inhibitor 1. Diabete Metabol 1987; 13: 331-336
• 10 Juhan-Vague I, Roul C, Alessi MC, Ardissone JP, Heim M, Vague P. Increased plasminogen activator inhibitor activity in non-insulin-dependent diabetic patients. Relationship with plasma insulin. Thromb Haemostas 1989; 61: 370-373
• 11 Pyorala K. Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease. Results from two population studies in Finland. Diabetes Care 1979; 2: 131-141
• 12 Welbom TA, Weane K. Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care 1979; 2: 154-160
• 13 Papoz L, Richard JL, Claude JR, Rosseling 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
• 14 Froesch ER, Zapf J. Insulin-like growth factors and insulin: compara tive aspects. Diabetologia 1985; 28: 485-493
• 15 Holly JMP, Wass JAH. Insulin-like growth factors; autocrine, para crine or endocrine? New perspectives of the somatomedin hypothesis in the light of recent developments. J Endocrinol 1989; 122: 611-618
• 16 Giacca A, Gupta R, Efendic S, Hall K, Skottner A, Lickley L. et al. Differential effects of IGF-1 and insulin on glucoregulation and fat metabolism in depancreatized dogs. Diabetes 1990; 39: 340-347
• 17 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 in hyperinsulinaemic states. Proc Natl Acad Sci 1991; 88: 9959-9963
• 18 Wright AD, Hill DM, Lowy C, Russell FraserT. Mortality in acromegaly. Q J Med 1970; NS 39 153: 01-16
• 19 Medcalf RL, van den Berg EA, Schleuning W-D. Glucocorticoid modulated gene expression of tissue- and urinary-type plasminogen activator and plasminogen activator inhibitor 1 and 2. J Cell Biol 1988; 106: 971-978
• 20 Minty A-J, Alonso S, Guenet J-L, Buckingham M-E. Number and organization of acting related sequences in the mouse genome. J Mol Biol 1983; 167: 77-81
• 21 Orme SM, Sebastian JR, Oldroyd B. et al. Comparison of measures of body composition in a trial of low-dose growth hormone replacement therapy. Clin Endocrinol 1992; 37: 453-459
• 22 Zenobi PD, Jaeggi-Groisman SE, Riesen W, Rder ME, Froesch ER. Insulin-like growth factor-1 improves glucose and lipid metabolism in type 2 diabetes mellitus. J Clin Invest 1992; 90: 2234-2241
• 23 Verheijen JH, Mullaart E, Chang GTG, Kluft C, Wijngaards G. A simple, sensitive spectrophotometric assay for extrinsic (tissue-type) plasminogen activator applicable to measurements in plasma. Thromb Haemostas 1982; 48: 266-269
• 24 Nilsson IM, Hedner U, Pandolfi M. The measurement of fibrinolytic activities. In: Fibrinolytes and Antifibrinolytes. Markward F. ed. Berlin: Springer; 1978: 107-134
• 25 Furlanetto RW, Underwood LE, Van WyckJJ, D’Ercole J. Estima tion of somatomedin C levels in normals and patients with pituitary disease by radioimmunoassay. J Clin Invest 1977; 60: 648-657
• 26 Bristow AF, Gooding RP, Gaines Das RE. The International reference reagent for insulin-like growth factor-1. J Endocrinol 1990; 125: 191-197
• 27 Zenobi PD, Graf S, Ursorung H, Froesch ER. Effects of insulin-like growth factor-1 on glucose tolerance, insulin levels and insulin secretion. J Clin Invest 1992; 89: 1908-1913
• 28 Stout RW, Vallance-Owen J. Insulin and atheroma. Lancet 1971; i: 1078
• 29 Jarret RJ. Is insulin atherogenic?. Diabetologia 1988; 31: 20
• 30 Duff GL, McMillan GC. The effect of alloxan diabetes on experimental atherosclerosis in the rabbit. I. The inhibition of experimental atherosclerosis in alloxan diabetes. II. The effect of alloxan diabetes on the regression of experimental cholesterol atherosclerosis J Exp Med 1949; 89: 611-630
• 31 Marquie G. Effect of insulin in the induction and regression of experimental cholesterol atherosclerosis in the rabbit. Postgrad Med J 1978; 54: 80-85
• 32 Grant PJ, Kruithof EKO, 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 Sci 1990; 79: 513-516
• 33 Potter van Loon BJ, de Bart ACW, Radder JK, Frolich M, Kluft C, Meinders AE. Acute exogenous hyperinsulinaemia does not result in elevation of plasma plasminogen activator inhibitor-1 (PAI-1) in humans. Fibrinolysis 1990; 4 (Suppl. 02) 93-94
• 34 Landin K, Tengborn L, Chmielewska J, von SchenckH, Smith U. The acute effect on insulin on tissue plasminogen activator and plasmino gen activator inhibitor in man. Thromb Haemostas 1991; 65: 130-133
• 35 Bornfeldt KE, Gidlöf RA, Wasteson A, Lake M, Skottner A, Arnqvist HJ. Binding and biological effects of insulin, insulin analo gues and insulin-like growth factors in rat aortic smooth muscle cells. Comparison of maximal growth promoting activities. Diabetologia 1991; 34: 307-313
• 36 Salamon EA, Luo J, Murphy LJ. The effect of acute and chronic insulin administration on insulin-like growth factor-1 expression in the pituitary intact and hypophysectomised rat. Diabetologia 1989; 32: 348-354
• 37 Caro JF, Poulos J, Hoop O, Pories WJ, Flichinger EG, Sinha MK. Insulin-like growth factor 1 binding in hepatocytes from human liver, human hepatoma, and normal regenerating, and fetal liver. J Clin Invest 1988; 81: 976-981
• 38 Foss MC, Sead MJA, Paccola MGF, Paula FJA, Piccinato CE, Moreira AC. Peripheral glucose metabolism in acromegaly. J Clin Endocrinol Metab 1991; 72: 1048-1053
• 39 Binnerts A, Deurenberg P, Swart GR, Wilson JHP, Lamberts WJ. Body composition in growth hormone deficient adults. Am J Clin Nutr 1992; 55: 918-923