mTORC1 signaling and regulation of pancreatic β-cell mass
Manuel Blandino-Rosano,Angela Y. Chen,Joshua O. Scheys,Emilyn U. Alejandro,Aaron P. Gould,Tatyana Taranukha,Lynda Elghazi,Corentin Cras-Méneur,Ernesto Bernal-Mizrachi +8 more
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TLDR
It is demonstrated that deletion of Tsc1 in pancreatic β cells results in improved glucose tolerance, hyperinsulinemia and expansion of β-cell mass that persists with aging.Abstract:
The capacity of β cells to expand in response to insulin resistance is a critical factor in the development of type 2 diabetes. Proliferation of β cells is a major component for these adaptive responses in animal models. The extracellular signals responsible for β-cell expansion include growth factors, such as insulin, and nutrients, such as glucose and amino acids. AKT activation is one of the important components linking growth signals to the regulation of β-cell expansion. Downstream of AKT, tuberous sclerosis complex 1 and 2 (TSC1/2) and mechanistic target of rapamycin complex 1 (mTORC1) signaling have emerged as prime candidates in this process, because they integrate signals from growth factors and nutrients. Recent studies demonstrate the importance of mTORC1 signaling in β cells. This review will discuss recent advances in the understanding of how this pathway regulates β-cell mass and present data on the role of TSC1 in modulation of β-cell mass. Herein, we also demonstrate that deletion of Tsc1 ...read more
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Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. [Erratum: 2004 Sept. 23, v. 431, no. 7007, p. 485.]
Sung Hee Um,Francesca Frigerio,Mitsuhiro Watanabe,Frédéric Picard,Manel Joaquin,Melanie Sticker,Stefano Fumagalli,Peter R. Allegrini,Sara C. Kozma,Johan Auwerx +9 more
TL;DR: In this article, S6K1-deficient mice are protected against obesity owing to enhanced β-oxidation, but on a high fat diet, levels of glucose and free fatty acids still rise in S6k1-dependent mice, resulting in insulin receptor desensitization.
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The emerging multiple roles of nuclear Akt
Alberto M. Martelli,Alberto M. Martelli,Giovanna Tabellini,Daniela Bressanin,Andrea Ognibene,Kaoru Goto,Lucio Cocco,Camilla Evangelisti +7 more
TL;DR: Evidence accumulated over the past 15 years has highlighted the presence of active Akt in the nucleus, where it acts as a fundamental component of key signaling pathways, and the most relevant findings about nuclear Akt are summarized.
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Insulin demand regulates β cell number via the unfolded protein response
Rohit Sharma,Amy C. O’Donnell,Rachel E. Stamateris,Binh Ha,Karen M. McCloskey,Paul R. Reynolds,Peter Arvan,Laura C. Alonso +7 more
TL;DR: A stem cell-independent model of tissue homeostasis is defined, in which differentiated secretory cells use the UPR sensor to adapt organ size to meet demand, suggesting that therapeutic UPR modulation has potential to expand β cell mass in people at risk for diabetes.
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mTORC1 Signaling: A Double-Edged Sword in Diabetic β Cells.
TL;DR: It is suggested that mTORC1 may act as a "double edge sword" in the regulation of β cell mass and function in response to metabolic stress such as nutrient overload and insulin resistance.
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Roles for PI3K/AKT/PTEN Pathway in Cell Signaling of Nonalcoholic Fatty Liver Disease
TL;DR: Molecular studies in the NAFLD support a key role for PTEN in hepatic insulin sensitivity and the development of steatosis, steatohepatitis, and fibrosis, and review recent studies on the features of the PTEN and the PI3K/AKT pathway.
References
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Journal ArticleDOI
Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway.
Brendan D. Manning,Brendan D. Manning,Andrew R. Tee,M. Nicole Logsdon,John Blenis,Lewis C. Cantley,Lewis C. Cantley +6 more
TL;DR: This approach identifies the tuberous sclerosis complex-2 gene product, tuberin, as a potential target of Akt/PKB, and demonstrates that, upon activation of PI3K, tuber in is phosphorylated on consensus recognition sites forPI3K-dependent S/T kinases.
Journal Article
Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. [Erratum: 2004 Sept. 23, v. 431, no. 7007, p. 485.]
Sung Hee Um,Francesca Frigerio,Mitsuhiro Watanabe,Frédéric Picard,Manel Joaquin,Melanie Sticker,Stefano Fumagalli,Peter R. Allegrini,Sara C. Kozma,Johan Auwerx +9 more
TL;DR: In this article, S6K1-deficient mice are protected against obesity owing to enhanced β-oxidation, but on a high fat diet, levels of glucose and free fatty acids still rise in S6k1-dependent mice, resulting in insulin receptor desensitization.
Journal ArticleDOI
Amino Acid Sufficiency and mTOR Regulate p70 S6 Kinase and eIF-4E BP1 through a Common Effector Mechanism
Kenta Hara,Kazuyoshi Yonezawa,Qing-Ping Weng,Mark T. Kozlowski,Christopher Belham,Joseph Avruch +5 more
TL;DR: The present study identifies the operation of a signal tranduction pathway in mammalian cells that provides a checkpoint control, linking amino acid sufficiency to the control of peptide chain initiation, indicating that mTOR is required for the response to amino acids.
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Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex
James Brugarolas,Kui Lei,Rebecca L. Hurley,Brendan D. Manning,Jan H. Reiling,Ernst Hafen,Lee A. Witters,Leif W. Ellisen,William G. Kaelin,William G. Kaelin +9 more
TL;DR: It is shown that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the Hypoxia-inducible gene REDD1/RTP801 to be inhibited, and that down-regulation of mTOR activity by hyp oxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxIA-Inducible REDD 1 gene.
Journal ArticleDOI
TSC2 Integrates Wnt and Energy Signals via a Coordinated Phosphorylation by AMPK and GSK3 to Regulate Cell Growth
Ken Inoki,Hongjiao Ouyang,Tianqing Zhu,Charlotta Lindvall,Yian Wang,Xiaojie Zhang,Qian Yang,Christina N. Bennett,Yuko Harada,Kryn Stankunas,Cun-Yu Wang,Xi He,Ormond A. MacDougald,Ming You,Bart O. Williams,Kun-Liang Guan +15 more
TL;DR: Results show that, in addition to transcriptional activation, Wnt stimulates translation and cell growth by activating the TSC-mTOR pathway, and the sequential phosphorylation of TSC2 by AMPK and GSK3 reveals a molecular mechanism of signal integration in cell growth regulation.