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291 REDUCED EXPRESSION OF P85α RESCUES 3T3-L1 ADIPOCYTES FROM THE INSULIN RESISTANCE INDUCED VIA SERINE PHOSPHORYLATION OF INSULIN RECEPTOR SUBSTRATE - 1 (IRS-1).
  1. R. Hedlund1,
  2. J. W. Leitner1,
  3. B. Draznin1
  1. 1Denver VA Medical Center and University of Colorado Health Sciences Center, Denver, CO.

Abstract

Serine (ser) phosphorylation of IRS-1 may be involved in a feedback inhibition of insulin signaling and, under certain circumstances, in the pathogenesis of insulin resistance (IR). On the other hand, variations in expression of p85α subunit of phosphatidylinositol (PI) 3-kinase could also modulate the strength of insulin signaling by altering the competition between the p85α monomer and the p85α-p110 heterodimer for the IRS-1 binding sites. In this study we examined the relationship between ser-phosphorylation of IRS-1 and expression of p85α in the development of IR in cultured 3T3 L1 adipocytes. IR was induced by the transfection of the constitutively active myristilated Akt (myr-Akt). Myr-Akt caused activation and phosphorylation of mTOR and p70S6 kinase. The latter promoted ser-phosphorylation of IRS-1 with a subsequent decline in its association with p85α and p110 as well as a decline in PI 3-kinase activity and insulin-stimulated 2-deoxyglucose (2-DOG) uptake-hence IR. A concomitant transfection of p85α siRNA reduced p85α expression by 70% and rescued insulin-stimulated 2DOG uptake from the inhibition induced by myr-Akt by diminishing the competition between p85α monomer and p85α-p110 heterodimer. In conclusion, IR induced by the Akt-mTOR-p70S6 kinase via ser-phosphorylation of IRS-1 can be ameliorated by a reduction in expression of p85α. Thus, interactions between ser-phosphorylation of IRS-1 and expression of p85α are important in the development of and the defense against IR.

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