Plasminogen Activator Inhibitor-1 Synthesis
نویسندگان
چکیده
High plasma plasminogen activator inhibitor-i (PAI-1) activity is associated with insulin resistance and is correlated with hyperinsulinemia. The cellular origin of plasma PAI-1 in insulin resistance is not known. The hepatoma cell line Hep G2 has been shown to synthesize PAI-1 in response to insulin. The aim of this study was to analyze the insulin-mediated response of PAI-1 and lipid synthesis in Hep G2 cells after producing an insulin-resistant state by decreasing insulin receptor numbers. The effect of metformin, a dimethyl-substituted biguanide, known to lower plasma insulin and PAI-I levels in vivo was concomitantly evaluated. Preincubation by an 18-h exposure of Hep G2 cells to 1i-7M insulin aimed at reducing the number of insulin receptors, was followed by a subsequent 24-h stimulation with 10-9M insulin. The decrease in insulin receptors was accompanied as expected, by a reduction in I14Clacetate incorporation, an index of lipid synthesis, whereas PAI-i secretion and PAI-i mRNA expression were enhanced. The addition of metformin did not modify the effect of insulin on insulin receptors or I14C acetate incorporation. In contrast, the drug (i0-4 M) inhibited insulin-mediated PAI-1 synthesis. The results indicate that PAI-1 synthesis in presence of insulin is markedly increased in down-regulated cells, and that metformin inhibits this effect by acting at the cellular level. These in vitro data are relevant with those found in vivo in insulin-resistant patients. Hep G2 cells may be a suitable model to study PAI-1 regulation in response to hyperinsulinemia. (J. Clin. Invest. 1993. 91:2185-2193.)
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