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Min Joo Kim  (Kim MJ) 2 Articles
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
  • 6,632 View
  • 115 Download
  • 14 Web of Science
  • 13 Crossref
AbstractAbstract 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.

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.

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
Others
Rg3 Improves Mitochondrial Function and the Expression of Key Genes Involved in Mitochondrial Biogenesis in C2C12 Myotubes
Min Joo Kim, Young Do Koo, Min Kim, Soo Lim, Young Joo Park, Sung Soo Chung, Hak C. Jang, Kyong Soo Park
Diabetes Metab J. 2016;40(5):406-413.   Published online August 12, 2016
DOI: https://doi.org/10.4093/dmj.2016.40.5.406
  • 4,888 View
  • 71 Download
  • 21 Web of Science
  • 22 Crossref
AbstractAbstract PDFPubReader   
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.

Methods

C2C12 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.

Results

Rg3 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.

Conclusion

Our 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.

Citations

Citations to this article as recorded by  
  • Comparison of Ginseng Leaf Extract and Its Acid-Treated Form, UG0712 Between Their Effects on Exercise Performance in Mice
    Young Jin Lee, Su Hyun Yu, Gwang Yeong Seok, Su Yeon Kim, Mi Jeong Kim, Inhye Jeong, Wan Heo, Bo Su Lee, Seon Gil Do, Bok Kyung Han, Young Jun Kim
    Food Supplements and Biomaterials for Health.2024;[Epub]     CrossRef
  • Ginsenosides for the treatment of insulin resistance and diabetes: Therapeutic perspectives and mechanistic insights
    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
    Tae-Ha Chung, Ji-Hye Kim, So-Young Seol, Yon-Ji Kim, Yong-Jae Lee
    Nutrients.2021; 13(9): 3090.     CrossRef
  • A comprehensive review on the phytochemistry, pharmacokinetics, and antidiabetic effect of Ginseng
    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
    Kyeong-Eun Yang, Hyun-Jin Jang, In-Hu Hwang, Eun Mi Hong, Min-Goo Lee, Soon Lee, Ik-Soon Jang, Jong-Soon Choi
    Journal of Ginseng Research.2020; 44(2): 341.     CrossRef
  • Ginsenosides for the treatment of metabolic syndrome and cardiovascular diseases: Pharmacology and mechanisms
    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
    W.F. Theeuwes, H.R. Gosker, R.C.J. Langen, K.J.P. Verhees, N.A.M. Pansters, A.M.W.J. Schols, A.H.V. Remels
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.2017; 1863(12): 3075.     CrossRef
  • Anti-Fatigue Effects of Small Molecule Oligopeptides Isolated from Panax ginseng C. A. Meyer in Mice
    Lei Bao, Xiaxia Cai, Junbo Wang, Yuan Zhang, Bin Sun, Yong Li
    Nutrients.2016; 8(12): 807.     CrossRef

Diabetes Metab J : Diabetes & Metabolism Journal