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Basic Research
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Diabetes Promotes Myocardial Fibrosis via AMPK/EZH2/PPAR-γ Signaling Pathway
Shan-Shan Li, Lu Pan, Zhen-Ye Zhang, Meng-Dan Zhou, Xu-Fei Chen, Ling-Ling Qian, Min Dai, Juan Lu, Zhi-Ming Yu, Shipeng Dang, Ru-Xing Wang
Diabetes Metab J. 2024;48(4):716-729.   Published online February 27, 2024
DOI: https://doi.org/10.4093/dmj.2023.0031
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AbstractAbstract PDFPubReader   ePub   
Background
Diabetes-induced cardiac fibrosis is one of the main mechanisms of diabetic cardiomyopathy. As a common histone methyltransferase, enhancer of zeste homolog 2 (EZH2) has been implicated in fibrosis progression in multiple organs. However, the mechanism of EZH2 in diabetic myocardial fibrosis has not been clarified.
Methods
In the current study, rat and mouse diabetic model were established, the left ventricular function of rat and mouse were evaluated by echocardiography and the fibrosis of rat ventricle was evaluated by Masson staining. Primary rat ventricular fibroblasts were cultured and stimulated with high glucose (HG) in vitro. The expression of histone H3 lysine 27 (H3K27) trimethylation, EZH2, and myocardial fibrosis proteins were assayed.
Results
In STZ-induced diabetic ventricular tissues and HG-induced primary ventricular fibroblasts in vitro, H3K27 trimethylation was increased and the phosphorylation of EZH2 was reduced. Inhibition of EZH2 with GSK126 suppressed the activation, differentiation, and migration of cardiac fibroblasts as well as the overexpression of the fibrotic proteins induced by HG. Mechanical study demonstrated that HG reduced phosphorylation of EZH2 on Thr311 by inactivating AMP-activated protein kinase (AMPK), which transcriptionally inhibited peroxisome proliferator-activated receptor γ (PPAR-γ) expression to promote the fibroblasts activation and differentiation.
Conclusion
Our data revealed an AMPK/EZH2/PPAR-γ signal pathway is involved in HG-induced cardiac fibrosis.

Citations

Citations to this article as recorded by  
  • An update on chronic complications of diabetes mellitus: from molecular mechanisms to therapeutic strategies with a focus on metabolic memory
    Tongyue Yang, Feng Qi, Feng Guo, Mingwei Shao, Yi Song, Gaofei Ren, Zhao Linlin, Guijun Qin, Yanyan Zhao
    Molecular Medicine.2024;[Epub]     CrossRef
  • Farrerol Alleviates Diabetic Cardiomyopathy by Regulating AMPK-Mediated Cardiac Lipid Metabolic Pathways in Type 2 Diabetic Rats
    Jia Tu, Qiaoling Liu, Huirong Sun, Luzhen Gan
    Cell Biochemistry and Biophysics.2024; 82(3): 2427.     CrossRef
Sulwon Lecture 2020
Pathophysiology
Article image
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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  • 8 Web of Science
  • 7 Crossref
Graphical AbstractGraphical Abstract AbstractAbstract PDFPubReader   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.

Citations

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  • 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
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    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
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    Respiratory Research.2023;[Epub]     CrossRef
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    Lei Wei, Jianjian Shi
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  • Paeoniflorin alleviates liver injury in hypercholesterolemic rats through the ROCK/AMPK pathway
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  • 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
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Original Articles
Complications
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Therapeutic Effects of Fibroblast Growth Factor-21 on Diabetic Nephropathy and the Possible Mechanism in Type 1 Diabetes Mellitus Mice
Wenya Weng, Tingwen Ge, Yi Wang, Lulu He, Tinghao Liu, Wanning Wang, Zongyu Zheng, Lechu Yu, Chi Zhang, Xuemian Lu
Diabetes Metab J. 2020;44(4):566-580.   Published online May 15, 2020
DOI: https://doi.org/10.4093/dmj.2019.0089
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  • 12 Web of Science
  • 11 Crossref
AbstractAbstract PDFPubReader   ePub   
Background

Fibroblast growth factor 21 (FGF21) has been only reported to prevent type 1 diabetic nephropathy (DN) in the streptozotocin-induced type 1 diabetes mellitus (T1DM) mouse model. However, the FVB (Cg)-Tg (Cryaa-Tag, Ins2-CALM1) 26OVE/PneJ (OVE26) transgenic mouse is a widely recommended mouse model to recapture the most important features of T1DM nephropathy that often occurs in diabetic patients. In addition, most previous studies focused on exploring the preventive effect of FGF21 on the development of DN. However, in clinic, development of therapeutic strategy has much more realistic value compared with preventive strategy since the onset time of DN is difficult to be accurately predicted. Therefore, in the present study OVE26 mice were used to investigate the potential therapeutic effects of FGF21 on DN.

Methods

Four-month-old female OVE26 mice were intraperitoneally treated with recombinant FGF21 at a dose of 100 µg/kg/day for 3 months. The diabetic and non-diabetic control mice were treated with phosphate-buffered saline at the same volume. Renal functions, pathological changes, inflammation, apoptosis, oxidative stress and fibrosis were examined in mice of all groups.

Results

The results showed that severe renal dysfunction, morphological changes, inflammation, apoptosis, and fibrosis were observed in OVE26 mice. However, all the renal abnormalities above in OVE26 mice were significantly attenuated by 3-month FGF21 treatment associated with improvement of renal adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) activity and sirtuin 1 (SIRT1) expression.

Conclusion

Therefore, this study demonstrated that FGF21 might exert therapeutic effects on DN through AMPK-SIRT1 pathway.

Citations

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  • Fibroblast growth factor 21 alleviates unilateral ureteral obstruction-induced renal fibrosis by inhibiting Wnt/β-catenin signaling pathway
    Wenhui Zhong, Yuheng Jiang, Huizhen Wang, Xiang Luo, Tao Zeng, Huimi Huang, Ling Xiao, Nan Jia, Aiqing Li
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.2024; 1871(2): 119620.     CrossRef
  • Urinary Excretion of Biomolecules Related to Cell Cycle, Proliferation, and Autophagy in Subjects with Type 2 Diabetes and Chronic Kidney Disease
    Anton I. Korbut, Vyacheslav V. Romanov, Vadim V. Klimontov
    Biomedicines.2024; 12(3): 487.     CrossRef
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    David M. Ornitz, Nobuyuki Itoh
    WIREs Mechanisms of Disease.2022;[Epub]     CrossRef
  • SIRT1–SIRT7 in Diabetic Kidney Disease: Biological Functions and Molecular Mechanisms
    Wenxiu Qi, Cheng Hu, Daqing Zhao, Xiangyan Li
    Frontiers in Endocrinology.2022;[Epub]     CrossRef
  • Research Progress of Fibroblast Growth Factor 21 in Fibrotic Diseases
    Min-Qi Jia, Cha-Xiang Guan, Jia-Hao Tao, Yong Zhou, Liang-Jun Yan
    Oxidative Medicine and Cellular Longevity.2022; 2022: 1.     CrossRef
  • Metabolic-associated fatty liver disease increases the risk of end-stage renal disease in patients with biopsy-confirmed diabetic nephropathy: a propensity-matched cohort study
    Yutong Zou, Lijun Zhao, Junlin Zhang, Yiting Wang, Yucheng Wu, Honghong Ren, Tingli Wang, Yuancheng Zhao, Huan Xu, Lin Li, Nanwei Tong, Fang Liu
    Acta Diabetologica.2022; 60(2): 225.     CrossRef
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    João Victor Salgado, Miguel Angelo Goes, Natalino Salgado Filho
    Metabolism.2021; 118: 154738.     CrossRef
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    Junyu Deng, Ye Liu, Yiqiu Liu, Wei Li, Xuqiang Nie
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    Fanrui Meng, Yukai Cao, Mir Hassan Khoso, Kai Kang, Guiping Ren, Wei Xiao, Deshan Li
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    Emma Henriksson, Birgitte Andersen
    Frontiers in Endocrinology.2020;[Epub]     CrossRef
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    Erik J. Tillman, Tim Rolph
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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
  • 7,588 View
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  • 15 Web of Science
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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.

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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
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    Lei Wei, Jianjian Shi
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Review
Complications
Autophagy: A Novel Therapeutic Target for Diabetic Nephropathy
Shinji Kume, Daisuke Koya
Diabetes Metab J. 2015;39(6):451-460.   Published online December 11, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.6.451
  • 5,845 View
  • 68 Download
  • 83 Web of Science
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AbstractAbstract PDFPubReader   

Diabetic nephropathy is a leading cause of end stage renal disease and its occurance is increasing worldwide. The most effective treatment strategy for the condition is intensive treatment to strictly control glycemia and blood pressure using renin-angiotensin system inhibitors. However, a fraction of patients still go on to reach end stage renal disease even under such intensive care. New therapeutic targets for diabetic nephropathy are, therefore, urgently needed. Autophagy is a major catabolic pathway by which mammalian cells degrade macromolecules and organelles to maintain intracellular homeostasis. The accumulation of damaged proteins and organelles is associated with the pathogenesis of diabetic nephropathy. Autophagy in the kidney is activated under some stress conditions, such as oxidative stress and hypoxia in proximal tubular cells, and occurs even under normal conditions in podocytes. These and other accumulating findings have led to a hypothesis that autophagy is involved in the pathogenesis of diabetic nephropathy. Here, we review recent findings underpinning this hypothesis and discuss the advantages of targeting autophagy for the treatment of diabetic nephropathy.

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Original Articles
Rosiglitazone Activates AMPK and Improves Non-Alcoholic Fatty Liver Disease in OLETF Rats.
Eun Hee Cho, Ki Up Lee
Korean Diabetes J. 2008;32(2):141-148.   Published online April 1, 2008
DOI: https://doi.org/10.4093/kdj.2008.32.2.141
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  • 1 Crossref
AbstractAbstract PDF
BACKGROUND
Insulin resistance is very common in patients with nonalcoholic fatty liver disease (NAFLD). Glitazones improve insulin sensitivity by acting as a selective agonist of the peroxisome proliferators -activated receptor gamma (PPAR gamma), and were shown to activate AMP-activated protein kinase (AMPK) in skeletal muscle and the liver. Glitazones were also shown to reduce hepatic lipogenesis. The aim of this study was to investigate whether the protective mechanism of rosiglitazone on NAFLD is associated with AMPK activation. METHODS: Twelve OLETF rats were divided into 2 groups (control, treatment, n = 6 each). LETO rats served as controls. At 35 weeks of age, treatment group received rosiglitazone 4 mg/kg daily for 3 days. Fasting plasma glucose, insulin, free fatty acid, lactate and triglycerides were measured. Liver tissues from each group were processed for histological and hepatic triglyceride content analysis and western blotting. RESULTS: Fasting plasma glucose, insulin and triglycerides levels were significantly lower in treatment group than in control group. Histologic examination disclosed decreased hepatic steatosis in treatment group. Hepatic triglyceride content was also decreased in treatment group. Sterol regulatory binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) expression were increased and AMPK phosphorylation was reduced in OLETF rats compared with LETO rats, and these changes were reversed by rosiglitazone treatment. CONCLUSION: Rosiglitazone reduced hepatic steatosis in OLETF rats, and activated AMPK in the liver. These results suggest the role of AMPK activation in the protective action of rosiglitazone on NAFLD.

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  • Small Rice Bowl-Based Meal Plan for Energy and Marcronutrient Intake in Korean Men with Type 2 Diabetes: A Pilot Study
    Hee Jung Ahn, Kyung Ah Han, Jin Young Jang, Jae Hyuk Lee, Kang Seo Park, Kyung Wan Min
    Diabetes & Metabolism Journal.2011; 35(3): 273.     CrossRef
AICAR Reversed the Glucolipotoxicity Induced beta-cell Dysfunction through Suppression of PPAR-gamma-coactivator-1 (PGC-1) Overexpression.
Hyuk Sang Kwon, Ji Won Kim, Heon Seok Park, Seung Hyun Ko, Bong Yun Cha, Ho Young Son, Kun Ho Yoon
Korean Diabetes J. 2007;31(4):310-318.   Published online July 1, 2007
DOI: https://doi.org/10.4093/jkda.2007.31.4.310
  • 2,191 View
  • 24 Download
AbstractAbstract PDF
BACKGROUND
Glucolipotoxicity plays an important role in the progression of type 2 diabetes mellitus via inducing insulin secretory dysfunction. Expression of insulin gene in pancreatic beta cell might be regulated by AMP-activated protein kinase (AMPK), which is recognized as a key molecule of energy metabolism. We studied the effects of AMPK on glucolipotoxicity-induced beta-cell dysfunction by suppression of PPAR-gamma-coactivator-1 (PGC-1) in vitro and in vivo. Method: Glucolipotoxicity was induced by 33.3 mM glucose and 0.6 mM (palmitate and oleate) for 3 days in isolated rat islets. Messenger RNA (mRNA) expressions of beta-cell specific gene like insulin, BETA2/NeuroD and PGC-1 induced by glucolipotoxic condition and their changes with 5-aminoimidazole-4-carboxy-amide-1-D-ribofuranoside (AICAR) treatment were investigated using RT-PCR. We also examined glucose stimulated insulin secretion in same conditions. Furthermore, SD rats were submitted to a 90% partial pancreatectomy (Px) and randomized into two groups; Ad-GFP-infected Px rats (n = 3) and Ad-siPGC- 1-infected Px rats (n = 3). Then, the Px rats were infected with Ad-GFP or Ad-siPGC-1 (1 x 10(9) pfu) via celiac artery. After 12 days of viral infection, we measured body weight and performed the intraperitoneal glucose tolerance test (IP-GTT). RESULTS: Glucolipotoxicity resulted in blunting of glucose-stimulated insulin secretion, which was recovered by the AICAR treatment in vitro. Suppression in their expressions of insulin and BETA2/NeuroD gene by glucolipotoxic condition were improved with AICAR treatment. However, PGC-1alpha expression was gradually increased by glucolipotoxicity, and suppressed by AICAR treatment. Overexpression of PGC-1 using an adenoviral vector in freshly isolated rat islets suppressed insulin gene expression. We also confirmed the function of PGC-1 using an Ad-siPGC-1 in vivo. Direct infection of Ad-siPGC-1 in 90% pancreatectomized rats significantly improved glucose tolerance and increased body weight. CONCLUSION: AMPK could protect against glucolipotoxicity induced beta-cell dysfunction and the suppression of PGC-1 gene expression might involved in the insulin regulatory mechanism by AMPK.
Hypothalamic AMPK Activity in Diabetic Rats.
Churl Namkoong, Min Seon Kim, Woo Je Lee, Pil Geum Jang, Seong Min Han, Eun Hee Koh, Joong Yeol Park, Ki Up Lee
Korean Diabetes J. 2004;28(6):468-477.   Published online December 1, 2004
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AbstractAbstract PDF
BACKGROUND
AMP-activated protein kinase (AMPK) acts as a cellular energy sensor that is activated during states of low energy charge and it regulates the various metabolic pathways to reestablish the normal cellular energy balance. It has recently been demonstrated that AMPK activity is altered by the state of energy metabolism in the hypothalamic neurons and this mediates the feeding response. METHODS: Diabetes was induced by an intra-peritoneal injection of streptozotocin (STZ) in Sprague-Dawley rats. The diabetic rats were maintained for 3 weeks with or without insulin treatment. 3 weeks later, we collected hypothalamus and we then assayed the phosphorylation of AMPK and the activity of acetyl CoA carboxylase (ACC) and isoform-specfic AMPK. To determine the effect of hypothalamic AMPK inhibition on diabetic hyperphagia, we administered an AMPK inhibitor, compound C, into the third ventricle in the STZ-induced diabetic rats. RESULTS: Phosphorylation of AMPK, which is a marker of AMPK activation, increased in the hypothalamus of the STZ-induced diabetic rats (DR). Moreover, 2-AMPK activity, but not 1-AMPK activity, increased by 2-fold in hypothalamus of the DRs. Phosphorylation of hypothalamic acetyl CoA carboxylase (ACC), a key downstream enzyme of AMPK, also increased in the DRs and this caused a reduction in ACC activity. Insulin treatment completely reversed the diabetesinduced changes in the hypothalamic AMPK and ACC, suggesting that insulin deficiency was associated with the changes in hypothalamic AMPK and ACC. Inhibition of AMPK by an intracerebroventricular administration of AMPK inhibitor, compound C, attenuated the development of diabetic hyperphagia and reduced the blood glucose levels in DRs. CONCLUSION: We have demonstrated that hypothalamic AMPK activity increased in the DRs, and inhibition of hypothalamic AMPK activity attenuated the development of diabetic hyperphagia. These data indicate that the enhanced hypothalamic AMPK activity may contribute to the development of diabetic hyperphagia

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