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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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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mTORC1 Signaling: A Double-Edged Sword in Diabetic β Cells.
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Roles for PI3K/AKT/PTEN Pathway in Cell Signaling of Nonalcoholic Fatty Liver Disease
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References
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mTORC1-Mediated Cell Proliferation, But Not Cell Growth, Controlled by the 4E-BPs
Ryan J.O. Dowling,Ivan Topisirovic,Tommy Alain,Michael Bidinosti,Bruno D. Fonseca,Emmanuel Petroulakis,Xiaoshan Wang,Ola Larsson,Anand Selvaraj,Yi Liu,Sara C. Kozma,George Thomas,Nahum Sonenberg +12 more
TL;DR: Control of cell size and cell cycle progression appear to be independent in mammalian cells, whereas in lower eukaryotes, 4E-BPs influence both cell growth and proliferation.
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Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase.
TL;DR: It is demonstrated that homozygous disruption of the p70s 6k/p85s6k gene does not affect viability or fertility of mice, but that it has a significant effect on animal growth, especially during embryogenesis, and the finding of a new S6 kinase gene, which can partly compensate for p70S6k/ p85s 6K function, underscores the importance of S6K function in cell growth.
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Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1
TL;DR: Filtration of amino acids into humans leads to S6K1 activation, inhibition of insulin-induced class 1 PI3K activation, and insulin resistance, and S 6K1 may mediate deleterious effects, like insulin resistance and potentially type 2 diabetes in the face of nutrient excess.
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Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis
Igor Ruvinsky,Nitzan Sharon,Tal Lerer,Hannah Cohen,Miri Stolovich-Rain,Tomer Nir,Yuval Dor,Philip Zisman,Oded Meyuhas +8 more
TL;DR: It is shown that contrary to the widely accepted model, this mutation does not affect the translational control of TOP mRNAs, and the size of rpS6(P-/-) MEFs, unlike wild-type MECs, is not further decreased upon rapamycin treatment, implying that the rPS6 is a critical downstream effector of mTOR in regulation of cell size.
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Skeletal Muscle-Specific Ablation of raptor, but Not of rictor, Causes Metabolic Changes and Results in Muscle Dystrophy
C. Florian Bentzinger,Klaas Romanino,Dimitri Cloëtta,Shuo Lin,Joseph B. Mascarenhas,Filippo Oliveri,Jinyu Xia,Emilio Casanova,Céline F. Costa,Marijke Brink,Francesco Zorzato,Michael N. Hall,Markus A. Rüegg +12 more
TL;DR: It is demonstrated that muscle mTORC1 has an unexpected role in the regulation of the metabolic properties and that its function is essential for life.