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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Phosphoproteomics Reveals the GSK3-PDX1 Axis as a Key Pathogenic Signaling Node in Diabetic Islets.
Francesca Sacco,Francesca Sacco,Anett Seelig,Sean J. Humphrey,Natalie Krahmer,Francesco Volta,Alessio Reggio,Piero Marchetti,Jantje M. Gerdes,Matthias Mann +9 more
TL;DR: Deep phosphoproteomic analysis of human islets chronically treated with high glucose demonstrated a conserved glucotoxicity-dependent role of GSK3 kinase in regulating insulin secretion, and the ability of beta cells to secrete insulin in response to glucose was rescued almost completely by pharmacological inhibition ofGSK3.
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Epidermal Growth Factor Receptor Signaling Promotes Pancreatic β-Cell Proliferation in Response to Nutrient Excess in Rats through mTOR and FOXM1
Bader Zarrouki,Isma Benterki,Ghislaine Fontés,Marie-Line Peyot,Ondrej Seda,Marc Prentki,Vincent Poitout +6 more
TL;DR: In this paper, a transcriptomic analysis identified a central role for the forkhead transcription factor FOXM1 and its targets, and for heparin-binding epidermal growth factor (EGF-like growth factor), a ligand of the EGF receptor (EGFR), in nutrient-induced β-cell proliferation.
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Systems Analysis of the Liver Transcriptome in Adult Male Zebrafish Exposed to the Plasticizer (2-Ethylhexyl) Phthalate (DEHP).
TL;DR: Exposure to low DEHP levels modulates the expression of liver genes related to fatty acid metabolism and the development of Non-Alcoholic Fatty Liver Disease (NAFLD).
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Overexpression of kinase-Dead mTOR Impairs Glucose Homeostasis by Regulating Insulin Secretion and Not β-Cell Mass
Emilyn U. Alejandro,Emilyn U. Alejandro,Nadejda Bozadjieva,Manuel Blandino-Rosano,Manuel Blandino-Rosano,Michelle Ann Wasan,Lynda Elghazi,Suryakiran Vadrevu,Leslie S. Satin,Ernesto Bernal-Mizrachi +9 more
TL;DR: The findings suggest that the mTOR-mediated signaling pathway is not essential to β-cell growth but is involved in regulating β- cell function in normal and diabetogenic conditions.
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Palmitate Induces mRNA Translation and Increases ER Protein Load in Islet β Cells via Activation of the Mammalian Target of Rapamycin Pathway
Masayuki Hatanaka,Bernhard Maier,Emily K. Sims,Andrew T. Templin,Rohit N. Kulkarni,Carmella Evans-Molina,Raghavendra G. Mirmira +6 more
TL;DR: This paper found that palmitate acutely increases polyribosome occupancy of total RNA, consistent with an increase in mRNA translation and that this increase in protein load contributes to the later unfolded protein response (UPR).
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