Clinical NephrologyChronic Inhibition of Mammalian Target of Rapamycin Signaling Downregulates Insulin Receptor Substrates 1 and 2 and AKT Activation A Crossroad between Cancer and Diabetes?Di Paolo, Salvatore; Teutonico, Annalisa; Leogrande, Domenica; Capobianco, Carmen; Schena, Paolo F. Author Information Department of Emergency and Organ Transplants, Division of Nephrology, Dialysis and Transplantation, University of Bari, Policlinico, Bari, Italy Address correspondence to: Dr. Salvatore Di Paolo, Department of Emergency and Organ Transplants, Division of Nephrology, Dialysis and Transplantation–University of Bari, Policlinico-Piazza Giulio Cesare, 11-70124 Bari, Italy. Phone: +39-080-5593231; Fax: +39-080-5593227; E-mail: [email protected] Accepted May 4, 2006 Received March 4, 2006 Journal of the American Society of Nephrology 17(8):p 2236-2244, August 2006. | DOI: 10.1681/ASN.2006030196 Buy Metrics Abstract Overactivation of the mammalian target of rapamycin (mTOR) branch downstream of the phosphatidylinositol 3-kinase–AKT pathway critically modulates insulin and growth factor signaling by insulin receptor substrates (IRS). On the basis of in vitro studies, the mTOR inhibitor rapamycin has been reported to lead to enhanced activation of AKT by relieving this feedback inhibition on IRS function. In view of the critical role of AKT in insulin signaling and tumorigenesis, the in vivo expression and activation of this kinase and of IRS-1 and IRS-2 were explored in PBMC of 30 patients who were treated long term with rapamycin. A marked decrease of basal and insulin-stimulated AKT phosphorylation, which correlated with the increase of patients’ insulin resistance, and a significant increase of IRS total protein expression, together with a lower (IRS-2) or absent (IRS-1) increase of insulin-induced tyrosine phosphorylation, were found. Therefore, contrary to the expectations, long-term exposure to rapamycin caused the impairment of IRS signaling and AKT activation, and this would help to explain the antiproliferative effect and the possible deterioration of glucose metabolism that are observed in rapamycin-treated patients. These findings may form a novel basis for improved understanding of the role of mTOR inhibition in human diseases, such as diabetes and cancer. Copyright © 2006 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.