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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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
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References
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Journal ArticleDOI
Rapamycin Has a Deleterious Effect on MIN-6 Cells and Rat and Human Islets
Ewan Bell,Xiaopei Cao,Jacob A. Moibi,Scott Greene,Robert J. Young,Matteo Trucco,Zhiyong Gao,Franz M. Matschinsky,Shaoping Deng,James F. Markman,Ali Naji,Bryan A. Wolf +11 more
TL;DR: A supra-therapeutic rapamycin concentration of 100 nmol/l significantly impaired glucose- and carbachol-stimulated insulin secretion in rat islets and had a deleterious effect on the viability of rat and human islets, causing apoptosis of both alpha- and beta-cells.
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Rictor/mTORC2 Is Essential for Maintaining a Balance Between β-Cell Proliferation and Cell Size
TL;DR: The phosphorylation of AKT-S473, by negatively regulating that ofAKT-T308, is essential for maintaining a balance between β-cell proliferation and cell size in response to proliferative stimuli.
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Different effects of FK506, rapamycin, and mycophenolate mofetil on glucose-stimulated insulin release and apoptosis in human islets.
James D. Johnson,Ziliang Ao,Peter Ao,Hong Li,Long-Jun Dai,Zehua He,May Tee,Kathryn J. Potter,Agnieszka M. Klimek,R. Mark Meloche,David M. Thompson,C. Bruce Verchere,Garth L. Warnock +12 more
TL;DR: It is shown that 24-h exposure to FK506 or MMF impairs glucose-stimulated insulin secretion in human islets and that immunosuppressants impair human β-cell function and survival, and that these defects can be circumvented to a certain extent with exenatide treatment.
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Activation of IRS-2—Mediated Signal Transduction by IGF-1, but not TGF-α or EGF, Augments Pancreatic β-Cell Proliferation
Melissa K. Lingohr,Lorna M. Dickson,Jill F. McCuaig,Sigrun R. Hügl,Daniel R. Twardzik,Christopher J. Rhodes +5 more
TL;DR: It was found that IGF-1 induced phosphatidylinositol 3-kinase (PI3K) association with insulin receptor substrate (IRS)-1 and -2 in a glucose-dependent manner, whereas TGF-α/EGF did not.
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Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1
Min Zheng,Yanhai Wang,Xiao-Nan Wu,Su-Qin Wu,Bao-Ju Lu,Meng-Qiu Dong,Hongbing Zhang,Peiqing Sun,Sheng-Cai Lin,Kun-Liang Guan,Jiahuai Han +10 more
TL;DR: It is shown that p38β–PRAK operates independently of the known mTORC1 inactivation pathways—phosphorylation of tuberous sclerosis protein 2 (TSC2) and Raptor by AMP-activated protein kinase (AMPK)—and surprisingly, that PRAK directly regulates Ras homologue enriched in brain (Rheb), a key component of the m TORC1 pathway, by phosphorylation.