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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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.
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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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Journal ArticleDOI
Disruption of Tsc2 in pancreatic β cells induces β cell mass expansion and improved glucose tolerance in a TORC1-dependent manner
Latif Rachdi,Norman Balcazar,Fernando Osorio-Duque,Lynda Elghazi,Aaron J. Weiss,Aaron P. Gould,Karen J. Chang-Chen,Michael J. Gambello,Ernesto Bernal-Mizrachi +8 more
TL;DR: A critical role is uncovered for the Tsc2/mTOR pathway in regulation of β cell mass and carbohydrate metabolism in vivo and inhibition of the mTOR/Raptor (TORC1) complex with rapamycin treatment suggests that TORC1 mediates proliferative and growth signals induced by deletion of T sc2 in β cells.
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SKAR is a specific target of S6 kinase 1 in cell growth control.
Celeste J. Richardson,Mark Broenstrup,Mark Broenstrup,Diane C. Fingar,Kristina Jülich,Kristina Jülich,Bryan A. Ballif,Steven P. Gygi,John Blenis +8 more
TL;DR: A novel and specific target of S6K1, SKAR, which regulates cell growth is identified, and the homology of SKAR to the Aly/REF family links S 6K1 with mRNA biogenesis in the control of cell growth.
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Signaling Elements Involved in the Metabolic Regulation of mTOR by Nutrients, Incretins, and Growth Factors in Islets
TL;DR: The hypothesis that incretin-derived cAMP participates in the metabolic activation of mTOR by mobilizing intracellular Ca2+ stores that upregulate mitochondrial dehydrogenases and result in enhanced ATP production is supported.
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The Role of Hypothalamic Mammalian Target of Rapamycin Complex 1 Signaling in Diet-Induced Obesity
TL;DR: Findings point strongly to the possibility that reduced hypothalamic mTORC1 signaling contributes to the development of hyperphagia, weight gain, and leptin resistance during diet-induced obesity.
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Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway.
Mirian Ueno,José B.C. Carvalheira,Rosa C. Tambascia,Rosângela Maria Neves Bezerra,Maria Esméria Corezola do Amaral,Everardo M. Carneiro,Franco Folli,Kleber G. Franchini,Mja Saad +8 more
TL;DR: Evidence is provided that chronic hyperinsulinaemia itself, imposed on normal rats, appears to have a dual effect, stimulating insulin signalling in white adipose tissue, whilst decreasing it in liver and muscle, and the hypothesis that defective and tissue-selective insulin action contributes to the insulin resistance observed in hyperinsulaemic states is supported.