Cbl, IRS-1, and IRS-2 mediate effects of rosiglitazone on PI3K, PKC-lambda, and glucose transport in 3T3/L1 adipocytes

Endocrinology. 2002 May;143(5):1705-16. doi: 10.1210/endo.143.5.8812.


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-lambda; accompanied by increases in tyrosine phosphorylation of Cbl and Cbl-dependent increases in PI3K and PKC-lambda 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-lambda and protein kinase B. Our findings suggest that Cbl participates in mediating effects of rosiglitazone on PI3K, PDK-1, and PKC-lambda 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-lambda during combined actions of rosiglitazone and insulin in 3T3/L1 cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Adipocytes / drug effects
  • Adipocytes / enzymology
  • Adipocytes / metabolism*
  • Animals
  • Antimetabolites
  • Biological Transport, Active / drug effects
  • Blotting, Western
  • Deoxyglucose
  • Enzyme Activation / drug effects
  • Glucose / metabolism*
  • Insulin / pharmacology
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes
  • Mice
  • Phosphatidylinositol 3-Kinases / drug effects*
  • Phosphoproteins / drug effects*
  • Phosphoproteins / genetics
  • Protein Kinase C / biosynthesis
  • Protein Kinase C / metabolism*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rosiglitazone
  • Signal Transduction / drug effects
  • Thiazoles / pharmacology*
  • Thiazolidinediones*


  • Antimetabolites
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs1 protein, mouse
  • Irs2 protein, mouse
  • Isoenzymes
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Thiazoles
  • Thiazolidinediones
  • Rosiglitazone
  • Deoxyglucose
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C
  • protein kinase C lambda
  • Glucose