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Cbl, IRS-1, and IRS-2 Mediate Effects of Rosiglitazone on PI3K, PKC-, and Glucose Transport in 3T3/L1 Adipocytes

J. A. Haley Veterans’ Hospital Research Service and Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida 33612

Address all correspondence and requests for reprints to: Robert V. Farese, M.D., Research Service (VAR 151), J. A. Haley Veterans’ Hospital, 13000 Bruce B. Downs Boulevard, Tampa, Florida 33612. E-mail: . rfarese{at}com1.med.usf.edu

The thiazolidenedione, rosiglitazone, increases basal and/or insulin-stimulated glucose transport in various cell types by diverse but uncertain mechanisms that may involve insulin receptor substrate (IRS)-1-dependent PI3K. Presently, in 3T3/L1 adipocytes, rosiglitazone induced sizable increases in basal glucose transport that were: dependent on PI3K, 3-phosphoinositide-dependent protein kinase-1 (PDK-1), and PKC-; accompanied by increases in tyrosine phosphorylation of Cbl and Cbl-dependent increases in PI3K and PKC- activity; but not accompanied by increases in IRS-1/2-dependent PI3K or protein kinase B activity. Additionally, rosiglitazone increased IRS-1 and IRS-2 levels, thereby enhancing insulin effects on IRS-1- and IRS-2-dependent PI3K and downstream signaling factors PKC- and protein kinase B. Our findings suggest that Cbl participates in mediating effects of rosiglitazone on PI3K, PDK-1, and PKC- and the glucose transport system and that this Cbl-dependent pathway complements the IRS-1 and IRS-2 pathways for activating PI3K, PDK-1, and PKC- during combined actions of rosiglitazone and insulin in 3T3/L1 cells.

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