PMID- 12351422 OWN - NLM STAT- MEDLINE DCOM- 20021203 LR - 20220227 IS - 0012-1797 (Print) IS - 0012-1797 (Linking) VI - 51 IP - 10 DP - 2002 Oct TI - Metabolic and autocrine regulation of the mammalian target of rapamycin by pancreatic beta-cells. PG - 2877-85 AB - Mammalian target of rapamycin (mTOR) is a serine and threonine protein kinase that regulates numerous cellular functions, in particular, the initiation of protein translation. mTOR-mediated phosphorylation of both the translational repressor eukaryotic initiation factor 4E binding protein-1 and p70 S6 kinase are early events that control the translation initiation process. Rapamycin, an inhibitor of mTOR, is a potent immunosuppressant due, in part, to its ability to interfere with T-cell activation at the level of translation, and it has gained a prominent role in preventing the development and progression of rejection in pancreatic islet transplant recipients. The characterization of the insulin signaling cascade that modulates mTOR in insulin-sensitive tissues has been a major focus of investigation. Recently, the ability of nutrients, in particular the branched-chain amino acid leucine, to activate mTOR independent of insulin by a process designated as nutrient signaling has been identified. The beta-cell expresses components of the insulin signaling cascade and utilizes the metabolism of nutrients to affect insulin secretion. These combined transduction processes make the beta-cell an unique cell to study metabolic and autocrine regulation of mTOR signaling. Our studies have described the ability of insulin and IGFs in concert with the nutrients leucine, glutamine, and glucose to modulate protein translation through mTOR in beta-cells. These findings suggest that mitochondria-derived factors, ATP in particular, may be responsible for nutrient signaling. The significance of these findings is that the optimization of mitochondrial function is not only important for insulin secretion but may significantly impact the growth and proliferation of beta-cells through these mTOR signaling pathways. FAU - McDaniel, Michael L AU - McDaniel ML AD - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. mcdaniel@pathology.wustl.edu FAU - Marshall, Connie A AU - Marshall CA FAU - Pappan, Kirk L AU - Pappan KL FAU - Kwon, Guim AU - Kwon G LA - eng GR - DK55024/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PT - Review PL - United States TA - Diabetes JT - Diabetes JID - 0372763 RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Autocrine Communication/*physiology MH - Islets of Langerhans/*enzymology MH - Mammals MH - Protein Kinases/*metabolism MH - TOR Serine-Threonine Kinases RF - 51 EDAT- 2002/09/28 04:00 MHDA- 2002/12/04 04:00 CRDT- 2002/09/28 04:00 PHST- 2002/09/28 04:00 [pubmed] PHST- 2002/12/04 04:00 [medline] PHST- 2002/09/28 04:00 [entrez] AID - 10.2337/diabetes.51.10.2877 [doi] PST - ppublish SO - Diabetes. 2002 Oct;51(10):2877-85. doi: 10.2337/diabetes.51.10.2877.