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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 297/5/E1013    most recent 00262.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Mori, H. Articles by Guan, K.-L. PubMed PubMed Citation Articles by Mori, H. Articles by Guan, K.-L.

Critical roles for the TSC-mTOR pathway in β-cell function

¹Life Sciences Institute, ²Department of Molecular and Integrative Physiology, ³Department of Medicine, ⁴Program in Neuroscience, ⁶Department of Biological Chemistry, and ⁷Institute of Gerontology, University of Michigan, Ann Arbor, Michigan; ⁵Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and ⁸Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA

Submitted 27 April 2009 ; accepted in final form 15 August 2009

TSC1 is a tumor suppressor that associates with TSC2 to inactivate Rheb, thereby inhibiting signaling by the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). mTORC1 stimulates cell growth by promoting anabolic cellular processes, such as translation, in response to growth factors and nutrient signals. To test roles for TSC1 and mTORC1 in β-cell function, we utilized Rip2/Cre to generate mice lacking Tsc1 in pancreatic β-cells (Rip-Tsc1cKO mice). Although obesity developed due to hypothalamic Tsc1 excision in older Rip-Tsc1cKO animals, young animals displayed a prominent gain-of-function β-cell phenotype prior to the onset of obesity. The young Rip-Tsc1cKO animals displayed improved glycemic control due to mTOR-mediated enhancement of β-cell size, mass, and insulin production but not determinants of β-cell number (proliferation and apoptosis), consistent with an important anabolic role for mTOR in β-cell function. Furthermore, mTOR mediated these effects in the face of impaired Akt signaling in β-cells. Thus, mTOR promulgates a dominant signal to promote β-cell/islet size and insulin production, and this pathway is crucial for β-cell function and glycemic control.

tuberous sclerosis complex; mammalian target of rapamycin; pancreatic β-cell; conditional knockout mice; rat insulin promoter 2