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- Pathophysiology
- Metformin Ameliorates Lipotoxic β-Cell Dysfunction through a Concentration-Dependent Dual Mechanism of Action
- Hong Il Kim, Ji Seon Lee, Byung Kook Kwak, Won Min Hwang, Min Joo Kim, Young-Bum Kim, Sung Soo Chung, Kyong Soo Park
- Diabetes Metab J. 2019;43(6):854-866. Published online June 27, 2019
- DOI: https://doi.org/10.4093/dmj.2018.0179
- 6,677 View
- 115 Download
- 14 Web of Science
- 13 Crossref
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Abstract
PDF
PubReader Background Chronic exposure to elevated levels of free fatty acids contributes to pancreatic β-cell dysfunction. Although it is well known that metformin induces cellular energy depletion and a concomitant activation of AMP-activated protein kinase (AMPK) through inhibition of the respiratory chain, previous studies have shown inconsistent results with regard to the action of metformin on pancreatic β-cells. We therefore examined the effects of metformin on pancreatic β-cells under lipotoxic stress.
Methods NIT-1 cells and mouse islets were exposed to palmitate and treated with 0.05 and 0.5 mM metformin. Cell viability, glucose-stimulated insulin secretion, cellular adenosine triphosphate, reactive oxygen species (ROS) levels and Rho kinase (ROCK) activities were measured. The phosphorylation of AMPK was evaluated by Western blot analysis and mRNA levels of endoplasmic reticulum (ER) stress markers and NADPH oxidase (NOX) were measured by real-time quantitative polymerase chain reaction analysis.
Results We found that metformin has protective effects on palmitate-induced β-cell dysfunction. Metformin at a concentration of 0.05 mM inhibits NOX and suppresses the palmitate-induced elevation of ER stress markers and ROS levels in a AMPK-independent manner, whereas 0.5 mM metformin inhibits ROCK activity and activates AMPK.
Conclusion This study suggests that the action of metformin on β-cell lipotoxicity was implemented by different molecular pathways depending on its concentration. Metformin at a usual therapeutic dose is supposed to alleviate lipotoxic β-cell dysfunction through inhibition of oxidative stress and ER stress.
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Citations
Citations to this article as recorded by
- Metformin enhances METTL14-Mediated m6A methylation to alleviate NIT-1 cells apoptosis induced by hydrogen peroxide
Si-min Zhou, Xin-ming Yao, Yi Cheng, Yu-jie Xing, Yue Sun, Qiang Hua, Shu-jun Wan, Xiang-jian Meng
Heliyon.2024; 10(2): e24432. CrossRef - Reduced Expression Level of Protein PhosphatasePPM1EServes to Maintain Insulin Secretion in Type 2 Diabetes
Sevda Gheibi, Luis Rodrigo Cataldo, Alexander Hamilton, Mi Huang, Sebastian Kalamajski, Malin Fex, Hindrik Mulder
Diabetes.2023; 72(4): 455. CrossRef - Metformin restores prohormone processing enzymes and normalizes aberrations in secretion of proinsulin and insulin in palmitate‐exposed human islets
Quan Wen, Azazul Islam Chowdhury, Banu Aydin, Mudhir Shekha, Rasmus Stenlid, Anders Forslund, Peter Bergsten
Diabetes, Obesity and Metabolism.2023; 25(12): 3757. CrossRef - Treatment of type 2 diabetes mellitus with stem cells and antidiabetic drugs: a dualistic and future-focused approach
Priyamvada Amol Arte, Kanchanlata Tungare, Mustansir Bhori, Renitta Jobby, Jyotirmoi Aich
Human Cell.2023; 37(1): 54. CrossRef - Metformin disrupts insulin secretion, causes proapoptotic and oxidative effects in rat pancreatic beta‐cells in vitro
Maíra M.R. Valle, Eloisa Aparecida Vilas‐Boas, Camila F. Lucena, Simone A. Teixeira, Marcelo N. Muscara, Angelo R. Carpinelli
Journal of Biochemical and Molecular Toxicology.2022;[Epub] CrossRef - Protection by metformin against severe Covid-19: An in-depth mechanistic analysis
Nicolas Wiernsperger, Abdallah Al-Salameh, Bertrand Cariou, Jean-Daniel Lalau
Diabetes & Metabolism.2022; 48(4): 101359. CrossRef - Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis
Lei Wei, Jianjian Shi
Frontiers in Endocrinology.2022;[Epub] CrossRef - Overexpression of miR-297b-5p Promotes Metformin-Mediated Protection Against Stearic Acid-Induced Senescence by Targeting Igf1r
Qingrui Zhao, Shenghan Su, Yuqing Lin, Xuebei Li, Lingfeng Dan, Yunjin Zhang, Chunxiao Yang, Xiaohan Li, Yimeng Dong, Chenchen Geng, Changhao Sun, Xia Chu, Huimin Lu
SSRN Electronic Journal .2022;[Epub] CrossRef - Metformin Dysregulates the Unfolded Protein Response and the WNT/β-Catenin Pathway in Endometrial Cancer Cells through an AMPK-Independent Mechanism
Domenico Conza, Paola Mirra, Gaetano Calì, Luigi Insabato, Francesca Fiory, Francesco Beguinot, Luca Ulianich
Cells.2021; 10(5): 1067. CrossRef - NADPH Oxidase (NOX) Targeting in Diabetes: A Special Emphasis on Pancreatic β-Cell Dysfunction
Suma Elumalai, Udayakumar Karunakaran, Jun-Sung Moon, Kyu-Chang Won
Cells.2021; 10(7): 1573. CrossRef - Metformin use and cardiovascular outcomes in patients with diabetes and chronic kidney disease: a nationwide cohort study
Min Ho Kim, Hyung Jung Oh, Soon Hyo Kwon, Jin Seok Jeon, Hyunjin Noh, Dong Cheol Han, Hyoungnae Kim, Dong-Ryeol Ryu
Kidney Research and Clinical Practice.2021; 40(4): 660. CrossRef - Different Effects of Metformin and A769662 on Sodium Iodate-Induced Cytotoxicity in Retinal Pigment Epithelial Cells: Distinct Actions on Mitochondrial Fission and Respiration
Chi-Ming Chan, Ponarulselvam Sekar, Duen-Yi Huang, Shu-Hao Hsu, Wan-Wan Lin
Antioxidants.2020; 9(11): 1057. CrossRef - Metformin Reduces Lipotoxicity-Induced Meta-Inflammation in β-Cells through the Activation of GPR40-PLC-IP3 Pathway
Ximei Shen, Beibei Fan, Xin Hu, Liufen Luo, Yuanli Yan, Liyong Yang
Journal of Diabetes Research.2019; 2019: 1. CrossRef
- Metformin enhances METTL14-Mediated m6A methylation to alleviate NIT-1 cells apoptosis induced by hydrogen peroxide
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