The effects of insulin-like growth factor-1 on plasminogen activator inhibitor-1 synthesis and secretion: results from in vitro and in vivo studies.
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/10(6) cells (range 21-91) to 144 ng/10(6) 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Padayatty
S J
SJ
Academic Unit of Medicine, General Infirmary at Leeds, UK.
Orme
S
S
Zenobi
P D
PD
Stickland
M H
MH
Belchetz
P E
PE
Grant
P J
PJ
D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D005342:Fibrinolysis / Q000187:drug effects; D013006:Growth Hormone / Q000627:therapeutic use*; D006801:Humans; D007018:Hypopituitarism / Q000097:blood / Q000188:drug therapy*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone