- Pathophysiology
- Metformin Ameliorates Lipotoxic β-Cell Dysfunction through a Concentration-Dependent Dual Mechanism of Action
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Hong Il Kim, Ji Seon Lee, Byung Kook Kwak, Won Min Hwang, Min Joo Kim, Young-Bum Kim, Sung Soo Chung, Kyong Soo Park
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Diabetes Metab J. 2019;43(6):854-866. Published online June 27, 2019
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DOI: https://doi.org/10.4093/dmj.2018.0179
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Abstract
PDFPubReader
- 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. MethodsNIT-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. ResultsWe 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. ConclusionThis 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
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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 - Roles of m6A modification in regulating PPER pathway in cadmium-induced pancreatic β cell death
Yifei Sun, Rongxian Li, Wenhong Li, Nan Zhang, Guofen Liu, Bo Zhao, Zongqin Mei, Shiyan Gu, Zuoshun He Ecotoxicology and Environmental Safety.2024; 282: 116672. 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
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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
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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
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- Others
- Rg3 Improves Mitochondrial Function and the Expression of Key Genes Involved in Mitochondrial Biogenesis in C2C12 Myotubes
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Min Joo Kim, Young Do Koo, Min Kim, Soo Lim, Young Joo Park, Sung Soo Chung, Hak C. Jang, Kyong Soo Park
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Diabetes Metab J. 2016;40(5):406-413. Published online August 12, 2016
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DOI: https://doi.org/10.4093/dmj.2016.40.5.406
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5,569
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Abstract
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- Background
Panax ginseng has glucose-lowering effects, some of which are associated with the improvement in insulin resistance in skeletal muscle. Because mitochondria play a pivotal role in the insulin resistance of skeletal muscle, we investigated the effects of the ginsenoside Rg3, one of the active components of P. ginseng, on mitochondrial function and biogenesis in C2C12 myotubes. MethodsC2C12 myotubes were treated with Rg3 for 24 hours. Insulin signaling pathway proteins were examined by Western blot. Cellular adenosine triphosphate (ATP) levels and the oxygen consumption rate were measured. The protein or mRNA levels of mitochondrial complexes were evaluated by Western blot and quantitative reverse transcription polymerase chain reaction analysis. ResultsRg3 treatment to C2C12 cells activated the insulin signaling pathway proteins, insulin receptor substrate-1 and Akt. Rg3 increased ATP production and the oxygen consumption rate, suggesting improved mitochondrial function. Rg3 increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor, which are transcription factors related to mitochondrial biogenesis. Subsequent increased expression of mitochondrial complex IV and V was also observed. ConclusionOur results suggest that Rg3 improves mitochondrial function and the expression of key genes involved in mitochondrial biogenesis, leading to an improvement in insulin resistance in skeletal muscle. Rg3 may have the potential to be developed as an anti-hyperglycemic agent.
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- Comparison of Ginseng Leaf Extract and Its Acid-Treated Form, UG0712 Between Their Effects on Exercise Performance in Mice
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Tae Hyun Kim Journal of Ginseng Research.2024; 48(3): 276. CrossRef - Preparation and bioactivity of the rare ginsenosides Rg3 and Rh2: An updated review
Wenqi Xu, Wei Lyu, Cuicui Duan, Fumin Ma, Xiaolei Li, Dan Li Fitoterapia.2023; 167: 105514. CrossRef - Ginsenoside Rc, an Active Component of Panax ginseng, Alleviates Oxidative Stress-Induced Muscle Atrophy via Improvement of Mitochondrial Biogenesis
Aeyung Kim, Sang-Min Park, No Soo Kim, Haeseung Lee Antioxidants.2023; 12(8): 1576. CrossRef - Ginsenoside Rg3 protects glucocorticoid‑induced muscle atrophy in vitro through improving mitochondrial biogenesis and myotube growth
Ryuni Kim, Jee Kim, Sang-Jin Lee, Gyu-Un Bae Molecular Medicine Reports.2022;[Epub] CrossRef - Beneficial Effects of Walnut Oligopeptides on Muscle Loss in Senescence-Accelerated Mouse Prone-8 (SAMP8) Mice: Focusing on Mitochondrial Function
Rui Fan, Yuntao Hao, Qian Du, Jiawei Kang, Meihong Xu, Yong Li Nutrients.2022; 14(10): 2051. CrossRef - Ginseng and ginsenosides: Therapeutic potential for sarcopenia
Weiwei Zha, Yuanhai Sun, Wenwen Gong, Linghuan Li, Wonnam Kim, Hanbing Li Biomedicine & Pharmacotherapy.2022; 156: 113876. CrossRef - Bioactive Oligopeptides from Ginseng (Panax ginseng Meyer) Suppress Oxidative Stress-Induced Senescence in Fibroblasts via NAD+/SIRT1/PGC-1α Signaling Pathway
Na Zhu, Mei-Hong Xu, Yong Li Nutrients.2022; 14(24): 5289. CrossRef - Review of ginsenosides targeting mitochondrial function to treat multiple disorders: Current status and perspectives
Qingxia Huang, Song Gao, Daqing Zhao, Xiangyan Li Journal of Ginseng Research.2021; 45(3): 371. CrossRef - The Effects of Korean Red Ginseng on Biological Aging and Antioxidant Capacity in Postmenopausal Women: A Double-Blind Randomized Controlled Study
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Yage Liu, Hao Zhang, Xuan Dai, Ruyuan Zhu, Beibei Chen, Bingke Xia, Zimengwei Ye, Dandan Zhao, Sihua Gao, Alexander N. Orekhov, Dongwei Zhang, Lili Wang, Shuzhen Guo Phytomedicine.2021; 92: 153717. CrossRef - Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes
Federica Zatterale, Michele Longo, Jamal Naderi, Gregory Alexander Raciti, Antonella Desiderio, Claudia Miele, Francesco Beguinot Frontiers in Physiology.2020;[Epub] CrossRef - Stereoisomer-specific ginsenoside 20(S)-Rg3 reverses replicative senescence of human diploid fibroblasts via Akt-mTOR-Sirtuin signaling
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Wenxiang Fan, Yongliang Huang, Hui Zheng, Shuiqin Li, Zhuohong Li, Li Yuan, Xi Cheng, Chengshi He, Jianfeng Sun Biomedicine & Pharmacotherapy.2020; 132: 110915. CrossRef - Ca2+-activated mitochondrial biogenesis and functions improve stem cell fate in Rg3-treated human mesenchymal stem cells
Taeui Hong, Moon Young Kim, Dat Da Ly, Su Jung Park, Young Woo Eom, Kyu-Sang Park, Soon Koo Baik Stem Cell Research & Therapy.2020;[Epub] CrossRef - Mitochondrial Dysfunction in Adipocytes as a Primary Cause of Adipose Tissue Inflammation
Chang-Yun Woo, Jung Eun Jang, Seung Eun Lee, Eun Hee Koh, Ki-Up Lee Diabetes & Metabolism Journal.2019; 43(3): 247. CrossRef - Ginsenoside Rg3 upregulates myotube formation and mitochondrial function, thereby protecting myotube atrophy induced by tumor necrosis factor-alpha
Sang-Jin Lee, Ju Hyun Bae, Hani Lee, Hyunji Lee, Jongsun Park, Jong-Sun Kang, Gyu-Un Bae Journal of Ethnopharmacology.2019; 242: 112054. CrossRef - Therapeutic Potential of Ginsenosides as an Adjuvant Treatment for Diabetes
Litao Bai, Jialiang Gao, Fan Wei, Jing Zhao, Danwei Wang, Junping Wei Frontiers in Pharmacology.2018;[Epub] CrossRef - Ginseng and obesity
Zhipeng Li, Geun Eog Ji Journal of Ginseng Research.2018; 42(1): 1. CrossRef - Molecular signaling of ginsenosides Rb1, Rg1, and Rg3 and their mode of actions
Padmanaban Mohanan, Sathiyamoorthy Subramaniyam, Ramya Mathiyalagan, Deok-Chun Yang Journal of Ginseng Research.2018; 42(2): 123. CrossRef - Inactivation of glycogen synthase kinase-3β (GSK-3β) enhances skeletal muscle oxidative metabolism
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Lei Bao, Xiaxia Cai, Junbo Wang, Yuan Zhang, Bin Sun, Yong Li Nutrients.2016; 8(12): 807. CrossRef
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