Diabetes & Metabolism Journal

Sulwon Lecture 2020

Pathophysiology
Rho-Kinase as a Therapeutic Target for Nonalcoholic Fatty Liver Diseases: Inês Sousa-Lima, Hyun Jeong Kim, John Jones, Young-Bum Kim; Diabetes Metab J. 2021;45(5):655-674. Published online September 30, 2021; DOI: https://doi.org/10.4093/dmj.2021.0197

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Graphical Abstract Abstract PDF PubReader ePub

Nonalcoholic fatty liver disease (NAFLD) is a major public health problem and the most common form of chronic liver disease, affecting 25% of the global population. Although NAFLD is closely linked with obesity, insulin resistance, and type 2 diabetes mellitus, knowledge on its pathogenesis remains incomplete. Emerging data have underscored the importance of Rho-kinase (Rho-associated coiled-coil-containing kinase [ROCK]) action in the maintenance of normal hepatic lipid homeostasis. In particular, pharmacological blockade of ROCK in hepatocytes or hepatic stellate cells prevents the progression of liver diseases such as NAFLD and fibrosis. Moreover, mice lacking hepatic ROCK1 are protected against obesity-induced fatty liver diseases by suppressing hepatic de novo lipogenesis. Here we review the roles of ROCK as an indispensable regulator of obesity-induced fatty liver disease and highlight the key cellular pathway governing hepatic lipid accumulation, with focus on de novo lipogenesis and its impact on therapeutic potential. Consequently, a comprehensive understanding of the metabolic milieu linking to liver dysfunction triggered by ROCK activation may help identify new targets for treating fatty liver diseases such as NAFLD.

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NORAD exacerbates metabolic dysfunction-associated steatotic liver disease development via the miR-511-3p/Rock2 axis and inhibits ubiquitin-mediated degradation of ROCK2
Xu Zhang, Tianxing Chen, Zhenhan Li, Lingfeng Wan, Zhihang Zhou, Ying Xu, Dong Yan, Wei Zhao, Hao Chen
Metabolism.2025; 164: 156111. CrossRef
THE ROLE OF N6-METHYLADENOSINE METHYLTRANSFERASE RBM15 IN NONALCOHOLIC FATTY LIVER DISEASE
Shiqing Li, Shengyi Lian, Wei Cheng, Tao Zhang, Xiaobing Gong
Shock.2024; 61(2): 311. CrossRef
Exploring the potential of drug repurposing for liver diseases: A comprehensive study
Fares E.M. Ali, Mustafa Ahmed Abdel-Reheim, Emad H.M. Hassanein, Mostafa K. Abd El-Aziz, Hanan S. Althagafy, Khalid S.A. Badran
Life Sciences.2024; 347: 122642. CrossRef
Targeting of G-protein coupled receptor 40 alleviates airway hyperresponsiveness through RhoA/ROCK1 signaling pathway in obese asthmatic mice
Xixi Lin, Like Wang, Xiaojie Lu, Yuanyuan Zhang, Rongying Zheng, Ruijie Chen, Weixi Zhang
Respiratory Research.2023;[Epub] CrossRef
Selectivity matters: selective ROCK2 inhibitor ameliorates established liver fibrosis via targeting inflammation, fibrosis, and metabolism
Alexandra Zanin-Zhorov, Wei Chen, Julien Moretti, Melanie S. Nyuydzefe, Iris Zhorov, Rashmi Munshi, Malavika Ghosh, Cindy Serdjebi, Kelli MacDonald, Bruce R. Blazar, Melissa Palmer, Samuel D. Waksal
Communications Biology.2023;[Epub] CrossRef
Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis
Lei Wei, Jianjian Shi
Frontiers in Endocrinology.2022;[Epub] CrossRef
Paeoniflorin alleviates liver injury in hypercholesterolemic rats through the ROCK/AMPK pathway
Tong Liu, Ning Zhang, Lingya Kong, Sijie Chu, Ting Zhang, Guangdi Yan, Donglai Ma, Jun Dai, Zhihong Ma
Frontiers in Pharmacology.2022;[Epub] CrossRef
Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation
Tingting Liao, Jingjing Deng, Wenjuan Chen, Juanjuan Xu, Guanghai Yang, Mei Zhou, Zhilei Lv, Sufei Wang, Siwei Song, Xueyun Tan, Zhengrong Yin, Yumei Li, Yang Jin
Cancers.2022; 14(19): 4709. CrossRef

Original Articles

Lifesytle
Combined Aerobic and Resistance Exercise Training Reduces Circulating Apolipoprotein J Levels and Improves Insulin Resistance in Postmenopausal Diabetic Women: Yun Kyung Jeon, Sang Soo Kim, Jong Ho Kim, Hyun Jeong Kim, Hyun Jun Kim, Jang Jun Park, Yuen Suk Cho, So Hee Joung, Ji Ryang Kim, Bo Hyun Kim, Sang Heon Song, In Joo Kim, Yong Ki Kim, Young-Bum Kim; Diabetes Metab J. 2020;44(1):103-112. Published online February 21, 2020; DOI: https://doi.org/10.4093/dmj.2018.0160

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Abstract PDF Supplementary Material PubReader

Background

Circulating apolipoprotein J (ApoJ) is closely associated with insulin resistance; however, the effect of exercise on circulating ApoJ levels and the association of ApoJ with metabolic indices remain unknown. Here, we investigated whether a combined exercise can alter the circulating ApoJ level, and whether these changes are associated with metabolic indices in patients with type 2 diabetes mellitus.

Methods

Postmenopausal women with type 2 diabetes mellitus were randomly assigned into either an exercise (EXE, n=30) or control (CON, n=15) group. Participants in the EXE group were enrolled in a 12-week program consisting of a combination of aerobic and resistance exercises. At baseline, 4, 8, and 12 weeks, body composition and metabolic parameters including homeostatic model assessment of insulin resistance (HOMA-IR) and serum ApoJ levels were assessed.

Results

In the EXE group, ApoJ levels decreased 26.3% and 19.4%, relative to baseline, at 8 and 12 weeks, respectively. Between-group differences were significant at 8 and 12 weeks (P<0.05 and P<0.001, respectively). In the EXE group, 12 weeks of exercise resulted in significant decreases in body weight, percent body fat, and HOMA-IR indices. Concurrently, weight-adjusted appendicular skeletal muscle mass (ASM/wt) was increased in the EXE group compared with the CON group. Importantly, changes in the ApoJ level were significantly correlated with changes in ASM/wt.

Conclusion

Exercise training resulted in a significant decrease in the circulating ApoJ level, with changes in ApoJ associated with an improvement in some insulin resistance indices. These data suggest that circulating ApoJ may be a useful metabolic marker for assessing the effects of exercise on insulin resistance.

Citations

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Xuepeng Bian, Qian Wang, Yibing Wang, Shujie Lou
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A randomized controlled trial of an app-based intervention on physical activity and glycemic control in people with type 2 diabetes
Gyuri Kim, Seohyun Kim, You-Bin Lee, Sang-Man Jin, Kyu Yeon Hur, Jae Hyeon Kim
BMC Medicine.2024;[Epub] CrossRef
Exercise modalities for type 2 diabetes: A systematic review and network meta‐analysis of randomized trials
Liangying Hou, Qi Wang, Bei Pan, Rui Li, Yanfei Li, Juanjuan He, Tianzhu Qin, Liujiao Cao, Na Zhang, Changhao Cao, Long Ge, Kehu Yang
Diabetes/Metabolism Research and Reviews.2023;[Epub] CrossRef
Estimating the Effect of Aerobic Exercise Training on Novel Lipid Biomarkers: A Systematic Review and Multivariate Meta-Analysis of Randomized Controlled Trials
Gina Wood, Emily Taylor, Vanessa Ng, Anna Murrell, Aditya Patil, Tom van der Touw, Mitch Wolden, Nick Andronicos, Neil A. Smart
Sports Medicine.2023; 53(4): 871. CrossRef
2023 update on Italian guidelines for the treatment of type 2 diabetes
Edoardo Mannucci, Riccardo Candido, Lina delle Monache, Marco Gallo, Andrea Giaccari, Maria Luisa Masini, Angela Mazzone, Gerardo Medea, Basilio Pintaudi, Giovanni Targher, Marina Trento, Giuseppe Turchetti, Valentina Lorenzoni, Matteo Monami
Acta Diabetologica.2023; 60(8): 1119. CrossRef
The Effect of Eight Weeks of Concurrent Training on Serum Levels of Paraxonase-1, Irisin, Lipid Profile, and Insulin Resistance in Men With Metabolic Syndrome
Seyed Amir Hosain Diba Hosaini, Morvarid Vafaee, Bahram Abedi
Hormozgan Medical Journal.2023; 27(1): 43. CrossRef
An Overview of the TRP-Oxidative Stress Axis in Metabolic Syndrome: Insights for Novel Therapeutic Approaches
Mizael C. Araújo, Suzany H. S. Soczek, Jaqueline P. Pontes, Leonardo A. C. Marques, Gabriela S. Santos, Gisele Simão, Laryssa R. Bueno, Daniele Maria-Ferreira, Marcelo N. Muscará, Elizabeth S. Fernandes
Cells.2022; 11(8): 1292. CrossRef
Effect of Yijinjing combined with elastic band exercise on muscle mass and function in middle-aged and elderly patients with prediabetes: A randomized controlled trial
Yunda Huang, Junhua Han, Qing Gu, Yanwei Cai, Jingyuan Li, Shasha Wang, Suijun Wang, Ru Wang, Xiangyun Liu
Frontiers in Medicine.2022;[Epub] CrossRef
Effect of combined aerobic and resistance exercise on blood pressure in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials
Huihui Xi, Yayu He, Yirou Niu, Xin Sui, Jun Zhang, Ruiting Zhu, Haiyan Xu, Shuang Zhang, Yang Li, Yuan Yuan, Lirong Guo
Experimental Gerontology.2021; 155: 111560. CrossRef
Effects of Augmented-Reality-Based Exercise on Muscle Parameters, Physical Performance, and Exercise Self-Efficacy for Older Adults
Sangwan Jeon, Jiyoun Kim
International Journal of Environmental Research and Public Health.2020; 17(9): 3260. CrossRef
Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity
Ji A Seo, Min-Cheol Kang, Won-Mo Yang, Won Min Hwang, Sang Soo Kim, Soo Hyun Hong, Jee-In Heo, Achana Vijyakumar, Leandro Pereira de Moura, Aykut Uner, Hu Huang, Seung Hwan Lee, Inês S. Lima, Kyong Soo Park, Min Seon Kim, Yossi Dagon, Thomas E. Willnow, V
Nature Communications.2020;[Epub] CrossRef
Impact of Skeletal Muscle Mass on Metabolic Health
Gyuri Kim, Jae Hyeon Kim
Endocrinology and Metabolism.2020; 35(1): 1. CrossRef
Habitual Combined Exercise Protects against Age-Associated Decline in Vascular Function and Lipid Profiles in Elderly Postmenopausal Women
Elizabeth J. Pekas, John Shin, Won-Mok Son, Ronald J. Headid, Song-Young Park
International Journal of Environmental Research and Public Health.2020; 17(11): 3893. CrossRef

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

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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.

Citations

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Metformin enhances METTL14-Mediated m6A methylation to alleviate NIT-1 cells apoptosis induced by hydrogen peroxide
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Ecotoxicology and Environmental Safety.2024; 282: 116672. CrossRef
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Hang Chen, Minshan Huang, Dan Zhang, Hui Wang, Da Wang, Mengwei Li, Xianmei Wang, Rui Zhu, Jianjun Liu, Lanqing Ma
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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
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Human Cell.2023; 37(1): 54. CrossRef
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Journal of Biochemical and Molecular Toxicology.2022;[Epub] CrossRef
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SSRN Electronic Journal .2022;[Epub] CrossRef
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Cells.2021; 10(5): 1067. CrossRef
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Cells.2021; 10(7): 1573. CrossRef
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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
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Ximei Shen, Beibei Fan, Xin Hu, Liufen Luo, Yuanli Yan, Liyong Yang
Journal of Diabetes Research.2019; 2019: 1. CrossRef

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