Document Detail


Critical roles for the TSC-mTOR pathway in β-cell function.
MedLine Citation:
PMID:  19690069     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Hiroyuki Mori; Ken Inoki; Darren Opland; Heike Münzberg; Eneida C Villanueva; Miro Faouzi; Tsuneo Ikenoue; David J Kwiatkowski; Ormond A Macdougald; Martin G Myers; Kun-Liang Guan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2009-08-18
Journal Detail:
Title:  American journal of physiology. Endocrinology and metabolism     Volume:  297     ISSN:  1522-1555     ISO Abbreviation:  Am. J. Physiol. Endocrinol. Metab.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2012-01-30     Completed Date:  2012-03-13     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  100901226     Medline TA:  Am J Physiol Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E1013-22     Citation Subset:  IM    
Affiliation:
Dept. of Pharmacology and Moores Cancer Center, Univ. of California San Diego, La Jolla, CA 92093-081, USA. kuguan@ucsd.edu
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MeSH Terms
Descriptor/Qualifier:
Aging / physiology
Animals
Anti-Bacterial Agents / pharmacology
Appetite / genetics,  physiology
Blood Glucose / metabolism
Blotting, Western
Cell Size
Immunohistochemistry
Insulin / metabolism
Insulin Resistance / genetics,  physiology
Insulin-Secreting Cells / physiology*
Mice
Mice, Knockout
Nerve Net / physiology
Obesity / genetics,  physiopathology
Signal Transduction / physiology
Sirolimus / pharmacology
TOR Serine-Threonine Kinases / genetics,  physiology*
Transcription Factors / genetics
Tumor Suppressor Proteins / genetics,  physiology*
Grant Support
ID/Acronym/Agency:
1 P01 CA120964/CA/NCI NIH HHS; DK-51563/DK/NIDDK NIH HHS; DK-56731/DK/NIDDK NIH HHS; DK-57768/DK/NIDDK NIH HHS; DK-62876/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Blood Glucose; 0/Crtc1 protein, mouse; 0/Insulin; 0/Transcription Factors; 0/Tumor Suppressor Proteins; 0/tuberous sclerosis complex 1 protein; 53123-88-9/Sirolimus; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.1.1/mTOR protein, mouse
Comments/Corrections

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