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Seoil Moon 2 Articles
Basic Research
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Glucolipotoxicity Suppressed Autophagy and Insulin Contents in Human Islets, and Attenuation of PERK Activity Enhanced Them in an ATG7-Dependent Manner
Seoil Moon, Ji Yoon Lim, Mirang Lee, Youngmin Han, Hongbeom Kim, Wooil Kwon, Jin-Young Jang, Mi Na Kim, Kyong Soo Park, Hye Seung Jung
Diabetes Metab J. 2024;48(2):231-241.   Published online September 6, 2023
DOI: https://doi.org/10.4093/dmj.2022.0366
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  • 231 Download
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Administration of pancreatic endoplasmic reticulum kinase inhibitor (PERKi) improved insulin secretion and hyperglycemia in obese diabetic mice. In this study, autophagic balance was studied whether to mediate it.
Methods
Human islets were isolated from living patients without diabetes. PERKi GSK2606414 effects were evaluated in the islets under glucolipotoxicity by palmitate. Islet insulin contents and secretion were measured. Autophagic flux was assessed by microtubule associated protein 1 light chain 3 (LC3) conversion, a red fluorescent protein (RFP)-green fluorescent protein (GFP)- LC3 tandem assay, and P62 levels. For mechanical analyses, autophagy was suppressed using 3-methyladenine in mouse islets. Small interfering RNA for an autophagy-related gene autophagy related 7 (Atg7) was transfected to interfere autophagy.
Results
PERKi administration to mice decreased diabetes-induced P62 levels in the islets. Glucolipotoxicity significantly increased PERK phosphorylation by 70% and decreased insulin contents by 50% in human islets, and addition of PERKi (40 to 80 nM) recovered both. PERKi also enhanced glucose-stimulated insulin secretion (6-fold). PERKi up-regulated LC3 conversion suppressed by glucolipotoxicity, and down-regulated P62 contents without changes in P62 transcription, indicating enhanced autophagic flux. Increased autophagosome-lysosome fusion by PERKi was visualized in mouse islets, where PERKi enhanced ATG7 bound to LC3. Suppression of Atg7 eliminated PERKi-induced insulin contents and secretion.
Conclusion
This study provided functional changes of human islets with regard to autophagy under glucolipotoxicity, and suggested modulation of autophagy as an anti-diabetic mechanism of PERKi.
Pathophysiology
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Endoplasmic Reticulum Stress and Dysregulated Autophagy in Human Pancreatic Beta Cells
Seoil Moon, Hye Seung Jung
Diabetes Metab J. 2022;46(4):533-542.   Published online July 27, 2022
DOI: https://doi.org/10.4093/dmj.2022.0070
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  • 258 Download
  • 12 Web of Science
  • 14 Crossref
AbstractAbstract PDFPubReader   ePub   
Pancreatic beta cell homeostasis is crucial for the synthesis and secretion of insulin; disruption of homeostasis causes diabetes, and is a treatment target. Adaptation to endoplasmic reticulum (ER) stress through the unfolded protein response (UPR) and adequate regulation of autophagy, which are closely linked, play essential roles in this homeostasis. In diabetes, the UPR and autophagy are dysregulated, which leads to beta cell failure and death. Various studies have explored methods to preserve pancreatic beta cell function and mass by relieving ER stress and regulating autophagic activity. To promote clinical translation of these research results to potential therapeutics for diabetes, we summarize the current knowledge on ER stress and autophagy in human insulin-secreting cells.

Citations

Citations to this article as recorded by  
  • Glucolipotoxicity Suppressed Autophagy and Insulin Contents in Human Islets, and Attenuation of PERK Activity Enhanced Them in an ATG7-Dependent Manner
    Seoil Moon, Ji Yoon Lim, Mirang Lee, Youngmin Han, Hongbeom Kim, Wooil Kwon, Jin-Young Jang, Mi Na Kim, Kyong Soo Park, Hye Seung Jung
    Diabetes & Metabolism Journal.2024; 48(2): 231.     CrossRef
  • Endoplasmic reticulum stress: A possible connection between intestinal inflammation and neurodegenerative disorders
    Giorgio Vivacqua, Romina Mancinelli, Stefano Leone, Rosa Vaccaro, Ludovica Garro, Simone Carotti, Ludovica Ceci, Paolo Onori, Luigi Pannarale, Antonio Franchitto, Eugenio Gaudio, Arianna Casini
    Neurogastroenterology & Motility.2024;[Epub]     CrossRef
  • Docosahexanoic Acid Attenuates Palmitate-Induced Apoptosis by Autophagy Upregulation via GPR120/mTOR Axis in Insulin-Secreting Cells
    Seok-Woo Hong, Jinmi Lee, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee
    Endocrinology and Metabolism.2024; 39(2): 353.     CrossRef
  • HIV-1 Tat-Mediated Human Müller Glial Cell Senescence Involves Endoplasmic Reticulum Stress and Dysregulated Autophagy
    Uma Maheswari Deshetty, Nivedita Chatterjee, Shilpa Buch, Palsamy Periyasamy
    Viruses.2024; 16(6): 903.     CrossRef
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    Tianxiang Zhang, Xi Zhang, Yang Fei, Jinsen Lu, Dairan Zhou, Li Zhang, Song Fan, Jun Zhou, Chaozhao Liang, Yang Su
    International Journal of Oncology.2024;[Epub]     CrossRef
  • Dysregulation of pancreatic β-cell autophagy and the risk of type 2 diabetes
    Hayder M. Al-kuraishy, Majid S. Jabir, Ali I. Al-Gareeb, Daniel J. Klionsky, Ali K. Albuhadily
    Autophagy.2024; : 1.     CrossRef
  • Endoplasmic reticulum stress mechanisms and exercise intervention in type 2 diabetes mellitus
    Qianyu Chen, Xiaoqin Zhao, Zujie Xu, Yiyao Liu
    Biomedicine & Pharmacotherapy.2024; 177: 117122.     CrossRef
  • Pancreatic islet remodeling in cotadutide-treated obese mice
    Renata Spezani, Thatiany Souza Marinho, Luiz E. Macedo Cardoso, Marcia Barbosa Aguila, Carlos Alberto Mandarim-de-Lacerda
    Life Sciences.2023; 327: 121858.     CrossRef
  • Modulation of Unfolded Protein Response Restores Survival and Function of β-Cells Exposed to the Endocrine Disruptor Bisphenol A
    Laura Maria Daian, Gabriela Tanko, Andrei Mircea Vacaru, Luiza Ghila, Simona Chera, Ana-Maria Vacaru
    International Journal of Molecular Sciences.2023; 24(3): 2023.     CrossRef
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    Min Jeong Park, Kyung Mook Choi
    Metabolism.2023; 144: 155577.     CrossRef
  • Identification and analysis of type 2 diabetes-mellitus-associated autophagy-related genes
    Kun Cui, Zhizheng Li
    Frontiers in Endocrinology.2023;[Epub]     CrossRef
  • Sestrin2 in diabetes and diabetic complications
    Xiaodan Zhang, Zirui Luo, Jiahong Li, Yaxuan Lin, Yu Li, Wangen Li
    Frontiers in Endocrinology.2023;[Epub]     CrossRef
  • Crosstalk between autophagy and insulin resistance: evidence from different tissues
    Asie Sadeghi, Maryam Niknam, Mohammad Amin Momeni-Moghaddam, Maryam Shabani, Hamid Aria, Alireza Bastin, Maryam Teimouri, Reza Meshkani, Hamed Akbari
    European Journal of Medical Research.2023;[Epub]     CrossRef
  • Beta cell lipotoxicity in the development of type 2 diabetes: the need for species-specific understanding
    Patricia Thomas, Meurig T. Gallagher, Gabriela Da Silva Xavier
    Frontiers in Endocrinology.2023;[Epub]     CrossRef

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