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
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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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.
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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
TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase.
Huira Chong-Kopera,Ken Inoki,Yong Li,Tianqing Zhu,Francesc R. Garcia-Gonzalo,Jose Luis Rosa,Kun-Liang Guan +6 more
TL;DR: A potential molecular mechanism of how TSC1 stabilizes TSC2 by excluding the HERC1 ubiquitin ligase from the T SC2 complex is revealed and a possible biochemical basis of how certain disease mutations inactivate TSC 2 is revealed.
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Metabolic Regulation by Leucine of Translation Initiation Through the mTOR-Signaling Pathway by Pancreatic β-Cells
TL;DR: Findings indicate that leucine at physiological concentrations stimulates p70s6k phosphorylation via the mTOR pathway, in part, by serving both as a mitochondrial fuel and an allosteric activator of GDH.
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Amino acid signalling and the integration of metabolism
TL;DR: It has become clear in recent years that amino acids are not only important as substrates for various metabolic pathways but that they can also activate a nutrient-sensitive, mTOR-mediated, signalling pathway in synergy with insulin, and thus contributes to the regulation of appetite.
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The Mammalian Target of Rapamycin Pathway Regulates Nutrient-Sensitive Glucose Uptake in Man
Michael Krebs,Barbara Brunmair,Attila Brehm,Michaela Artwohl,Julia Szendroedi,Peter Nowotny,Erich Roth,Clemens Fürnsinn,Miriam Promintzer,Christian Anderwald,Martin Bischof,Michael Roden +11 more
TL;DR: In conclusion, rapamycin stimulates insulin-mediated glucose uptake in man under conditions known to activate the mTOR/S6K pathway.
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Not all substrates are treated equally: implications for mTOR, rapamycin-resistance and cancer therapy.
Andrew Y. Choo,John Blenis +1 more
TL;DR: The implications of a recent finding that showed differential inhibition of S6K1 and 4E-BP1 by rapamycin, leading to cell-type-specific repression of cap-dependent translation are discussed, and it is proposed that mTOR-specific kinase inhibitors should be considered for m TOR-targeted cancer therapy.