Thiazolidinedione derivatives are insulin-sensitizing agents with proven antidiabetic activities in vivo. To explore the mechanism of action of this class of compounds, the effects of pioglitazone, CP-86,325, and AD-5075 on elements of the insulin signal transduction pathways were studied in Chinese hamster ovary cells overexpressing human insulin receptor (CHO-T) and L6 myotubes. In CHO-T cells, the binding of insulin to its receptor and the insulin-stimulated tyrosine kinase activity of the receptor were not altered by pioglitazone or CP-86,325. In contrast, treatment of CHO-T cells with the compounds resulted in significant increases in insulin-stimulated phosphatidylinositol (PI) 3-kinase activity. This insulin-enhancing effect was also observed in L6 myotubes treated with CP-86,325. The augmentations in kinase activity observed in CHO-T cells correlated with increases in the amount of PI 3-kinase (p85 subunit) in anti-phosphotyrosine immunoprecipitates of cell lysates. No gross changes in the tyrosine phosphorylation state of the insulin receptor substrate-1 were detected in insulin-stimulated CHO-T cells following treatment with the compounds. Furthermore, the compounds did not enhance insulin stimulation of mitogen- activated protein kinase or DNA synthesis in CHO-T cells. Thus, thiazolidinedione-derived antidiabetic agents may act as insulin sensitizers by augmenting insulin stimulation of PI 3-kinase activity in a rather specific manner.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of Biological Chemistry|
|State||Published - Oct 14 1994|
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