Phosphatidylinositol 3-kinase (PI3K) is a pivotal enzyme involved in the control of a variety of diverse metabolic functions. Glucocorticoids have been shown to attenuate PI3K signaling in some nonrenal cell types, raising the possibility that some physiologic effects of glucocorticoids in renal cells may be achieved by a similar mechanism. Therefore, we tested whether glucocorticoids affect signaling through the IRS-1/PI3K/Akt signaling cascade in LLC-PK1.GR101 renal epithelial cells. Treating cells with dexamethasone for 24 hrs: 1) suppressed IRS-1-associated PI3K activity and Akt phosphorylation; 2) increased the level of the PI3K p85 regulatory subunit, but not the p110 catalytic subunit; and 3) induced the phosphorylation of IRS-1 on inhibitory Ser³⁰⁷. We previously reported that glucocorticoids increase branched-chain ketoacid dehydrogenase (BCKD) activity in LLC-PK1.GR101 cells. This response was achieved, in part, by alterations in the transcription of BCKD subunits and BCKD kinase which inactivates the enzyme complex by phosphorylation. Therefore, we tested whether inhibition of PI3K signaling would mimick glucocorticoids by increasing branched-chain amino acid degradation. Expression of a dominant-negative PI3K p85 regulatory subunit (Adp85iSH2) increased BCKD activity and dexamethasone did not further stimulate enzyme activity. Inhibition of PI3K using Ly294002 increased the transcription of the BCKD E2 subunit but not the E1 subunit or BCKD kinase. Thus, glucocorticoids inhibit signaling through the IRS-1/PI3K/Akt pathway with a consequence of increased BCAA catabolism.