p8 is a novel intracellular mediator of pancreatic β-cell protection that preserves insulin secretory function during inflammatory cell stress in vivo

Background/Aims: Intermittent hypoxia (IH) causes apoptosis in pancreatic β-cells, but the potential mechanisms remain unclear. Endoplasmic reticulum (ER) stress, autophagy, and apoptosis are interlocked in an extensive crosstalk. Thus, this study aimed to investigate the contributions of ER stress and autophagy to IH-induced pancreatic β-cell apoptosis. Methods: We established animal and cell models of IH, and then inhibited autophagy and ER stress by pharmacology and small interfering RNA (siRNA) in INS-1 cells and rats. The levels of biomarkers for autophagy, ER stress, and apoptosis were evaluated by immunoblotting and immunofluorescence. The number of autophagic vacuoles was observed by transmission electron microscopy. Results: IH induced autophagy activation both in vivo and in vitro, as evidenced by increased autophagic vacuole formation and LC3 turnover, and decreased SQSTM1 level. The levels of ER-stress-related proteins, including GRP78, CHOP, caspase 12, phosphorylated (p)-protein kinase RNA-like ER kinase (PERK), p-eIF2α, and activating transcription factor 4 (ATF4) were increased under IH conditions. Inhibition of ER stress with tauroursodeoxycholic acid or 4-phenylbutyrate partially blocked IH-induced autophagy in INS-1 cells. Furthermore, inhibition of PERK with GSK2606414 or siRNA blocked the ERstress-related PERK/eIF2α/ATF4 signaling pathway and inhibited autophagy induced by IH, which indicates that IH-induced autophagy activation is dependent on this signaling pathway. Promoting autophagy with rapamycin alleviated IH-induced apoptosis, whereas inhibition of autophagy with chloroquine or autophagy-related gene (Atg5 and Atg7) siRNA aggravated pancreatic β-cell apoptosis caused by IH. Conclusion: IH induces autophagy activation through the ER-stress-related PERK/eIF2α/ATF4 signaling pathway, which is a protective response to pancreatic β-cell apoptosis caused by IH.

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Honokiol protects pancreatic β cell against high glucose and intermittent hypoxia-induced injury by activating Nrf2/ARE pathway in vitro and in vivo

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2017.11.063 ◽

2018 ◽

Vol 97 ◽

pp. 1229-1237 ◽

Cited By ~ 13

Author(s):

Chen-guang Li ◽

Chang-lin Ni ◽

Min Yang ◽

Yun-zhao Tang ◽

Zhu Li ◽

...

Keyword(s):

High Glucose ◽

Intermittent Hypoxia ◽

Pancreatic Β Cell ◽

Β Cell

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Role of AKT/mTORC1 pathway in pancreatic β-cell proliferation

Colombia Medica ◽

10.25100/cm.v43i3.783 ◽

2012 ◽

pp. 235-243 ◽

Cited By ~ 9

Author(s):

Norman Balcazar Morales ◽

Cecilia Aguilar de Plata

Keyword(s):

Cell Cycle ◽

Growth Factors ◽

Cell Cycle Progression ◽

Cell Mass ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cycle Progression ◽

Mtorc1 Signaling

Growth factors, insulin signaling and nutrients are important regulators of β-cell mass and function. The events linking these signals to regulation of β-cell mass are not completely understood. Recent findings indicate that mTOR pathway integrates signals from growth factors and nutrients with transcription, translation, cell size, cytoskeleton remodeling and mitochondrial metabolism. mTOR is a part of two distinct complexes; mTORC1 and mTORC2. The mammalian TORC1 is sensitive to rapamycin and contains Raptor, deptor, PRAS40 and the G protein β-subunit-like protein (GβL). mTORC1 activates key regulators of protein translation; ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E-binding protein 1. This review summarizes current findings about the role of AKT/mTORC1 signaling in regulation of pancreatic β cell mass and proliferation. mTORC1 is a major regulator of β-cell cycle progression by modulation of cyclins D2, D3 and cdk4/cyclin D activity. These studies uncovered key novel pathways controlling cell cycle progression in β-cells in vivo. This information can be used to develop alternative approaches to expand β-cell mass in vivo and in vitro without the risk of oncogenic transformation. The acquisition of such knowledge is critical for the design of improved therapeutic strategies for the treatment and cure of diabetes as well as to understand the effects of mTOR inhibitors in β-cell function.

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Measuring the Pancreatic β Cell Mass in Vivo with Exendin SPECT during Hyperglycemia and Severe Insulitis

Molecular Pharmaceutics ◽

10.1021/acs.molpharmaceut.9b00728 ◽

2019 ◽

Vol 16 (9) ◽

pp. 4024-4030 ◽

Cited By ~ 3

Author(s):

Lieke Joosten ◽

Maarten Brom ◽

Hanneke Peeters ◽

Desirée Bos ◽

Eddy Himpe ◽

...

Keyword(s):

Cell Mass ◽

Pancreatic Β Cell ◽

Β Cell

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Role of NF-κB in β-cell death

Biochemical Society Transactions ◽

10.1042/bst0360334 ◽

2008 ◽

Vol 36 (3) ◽

pp. 334-339 ◽

Cited By ~ 69

Author(s):

Danielle Melloul

Keyword(s):

Cell Death ◽

Lymphocytic Infiltration ◽

Nuclear Factor Κb ◽

Interferon Γ ◽

Cell Protection ◽

Β Cells ◽

Β Cell ◽

Ifn Γ ◽

Induced Apoptosis

Apoptotic β-cell death appears to be central to the pathogenesis of Type 1 diabetes mellitus and in islet graft rejection. The β-cell destruction is partially mediated by cytokines, such as IL-1β (interleukin 1β), TNFα (tumour necrosis factor α) and IFN-γ (interferon γ). IL-1β and TNFα mediate activation of the transcription factor NF-κB (nuclear factor κB) pathway. Use of a degradation-resistant NF-κB protein inhibitor (ΔNIκBα), specifically expressed in β-cells, significantly reduced IL-1β+IFN-γ-induced apoptosis. Moreover, in vivo, it protected against multiple low-dose streptozocin-induced diabetes, with reduced intra-islet lymphocytic infiltration. Thus β-cell-specific activation of NF-κB is a key event in the progressive loss of β-cells in diabetes. Inhibition of this process could be a potential effective strategy for β-cell protection.

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