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.
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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Insulin Receptor Substrate-2 Proteasomal Degradation Mediated by a Mammalian Target of Rapamycin (mTOR)-induced Negative Feedback Down-regulates Protein Kinase B-mediated Signaling Pathway in β-Cells
Isabelle Briaud,Lorna M. Dickson,Melissa K. Lingohr,Jill F. McCuaig,John C. Lawrence,Christopher J. Rhodes +5 more
TL;DR: Chronic activation of mTOR by glucose by glucose (and/or IGF-1) in β-cells leads to increased Ser/Thr phosphorylation of IRS-2 that targets it for proteasomal degradation, resulting in decreased IRS- 2 expression and increased β-cell apoptosis.
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mTORC1 Activation Regulates β-Cell Mass and Proliferation by Modulation of Cyclin D2 Synthesis and Stability
Norman Balcazar,Aruna Sathyamurthy,Lynda Elghazi,Aaron P. Gould,Aaron J. Weiss,Ichiro Shiojima,Kenneth Walsh,Ernesto Bernal-Mizrachi +7 more
TL;DR: These studies provide novel insights into the regulation of cell cycle by the mTORC1, provide a mechanism for the antiproliferative effects of rapamycin, and imply that the use of Rapamycin could negatively impact the success of islet transplantation and the adaptation of β-cells to insulin resistance.
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Chronic Inhibition of Mammalian Target of Rapamycin Signaling Downregulates Insulin Receptor Substrates 1 and 2 and AKT Activation: A Crossroad between Cancer and Diabetes?
TL;DR: Contrary to the expectations, long-term exposure to rapamycin caused the impairment of IRS signaling and AKT activation, and this would help to explain the antiproliferative effect and the possible deterioration of glucose metabolism that are observed inRapamycin-treated patients.
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Insulin Mediates Glucose-stimulated Phosphorylation of PHAS-I by Pancreatic Beta Cells AN INSULIN-RECEPTOR MECHANISM FOR AUTOREGULATION OF PROTEIN SYNTHESIS BY TRANSLATION
Guang Xu,Connie A. Marshall,Tai-An Lin,Guim Kwon,Raghava B. Munivenkatappa,Jeanette R. Hill,John C. Lawrence,Michael L. McDaniel +7 more
TL;DR: Results indicate that glucose stimulates PHAS-I phosphorylation via insulin interacting with its own receptor on the beta cell which may serve as an important mechanism for autoregulation of protein synthesis by translation.
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Rapamycin impairs in vivo proliferation of islet beta-cells.
E. Zahr,R. Damaris Molano,Antonello Pileggi,Hirohito Ichii,Sergio San Jose,N. Bocca,Weijun An,Jorge Gonzalez-Quintana,Christopher A. Fraker,Camillo Ricordi,Luca Inverardi +10 more
TL;DR: Pregnancy led to increased pancreatic islet cell proliferation and islet yield with skewing in islet size distribution as well as higher pancreatic insulin content, when compared to that of nonpregnant females, and the effects of pregnancy on &bgr;-cell proliferation and mass were significantly blunted by rapamycin treatment.