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
Citations
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Impact of short-term overfeeding and caloric restriction on gut permeability, gut microbiota composition, and metabolic function in humans
TL;DR: In essence, caloric restriction improves gut permeability and low-grade inflammation with minor impact on gut microbiota profiles, and short-term overfeeding does neither affect insulin sensitivity nor Gut permeability.
Posted ContentDOI
Furin controls β cell function via mTORC1 signaling
Bas Brouwers,Ilaria Coppola,Katlijn Vints,Bastian Dislich,Nathalie Jouvet,Leentje Van Lommel,Natalia V. Gounko,Lieven Thorrez,Frans Schuit,Stefan F. Lichtenthaler,Jennifer L. Estall,Jeroen Declercq,Bruno Ramos-Molina,John W.M. Creemers +13 more
TL;DR: It is shown that furin is highly expressed in human islets, while PCs that potentially could provide redundancy are expressed at considerably lower levels, which suggests a model of mTORC1-ATF4 hyperactivation in β cells lacking furin, which causes β cell dysfunction.
Book ChapterDOI
Leucine as a Stimulant of Insulin
TL;DR: Recent studies revealed that leucine is a potent activator of mTOR, which appears to regulate insulin release by influencing adrenergic activity via the mTOR pathway, which has been implicated in new-onset diabetes in renal transplant patients.
Journal ArticleDOI
Critical role for the Tsc1-mTORC1 pathway in β-cell mass in Pdx1-deficient mice.
TL;DR: In Pdx1-deficient mice, tuberous sclerosis 1 (Tsc1) ablation in pancreatic β-cells restores β-cell mass, increases β- cell proliferation and size, decreases the number of TUNEL-positive cells and restores glucose tolerance after glucose challenge, suggesting that mTORC1 may be target for therapeutic interventions in diabetes associated with reductions in β- Cell mass.
References
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Journal ArticleDOI
TOR signaling in growth and metabolism.
TL;DR: The physiological consequences of mammalianTORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
PatentDOI
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
TL;DR: In this paper, the rictor-mTOR complex was used to identify compounds which modulate Akt activity mediated by the Rictor mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activation.
Journal ArticleDOI
Upstream and downstream of mTOR
Nissim Hay,Nahum Sonenberg +1 more
TL;DR: Both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis are described.
Journal ArticleDOI
TSC2 mediates cellular energy response to control cell growth and survival.
TL;DR: It is described that TSC2 is regulated by cellular energy levels and plays an essential role in the cellular energy response pathway and its phosphorylation by AMPK protect cells from energy deprivation-induced apoptosis.
Journal ArticleDOI
AMPK phosphorylation of raptor mediates a metabolic checkpoint.
Dana M. Gwinn,David B. Shackelford,Daniel F. Egan,Maria M. Mihaylova,Annabelle Mery,Debbie S. Vasquez,Benjamin E. Turk,Reuben J. Shaw +7 more
TL;DR: AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor, uncovering a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status.