Diabetes & Metabolism Journal

Original Articles

Basic research
Reducing Oxidative Stress and Inflammation by Pyruvate Dehydrogenase Kinase 4 Inhibition Is Important in Prevention of Renal Ischemia-Reperfusion Injury in Diabetic Mice: Ah Reum Khang, Dong Hun Kim, Min-Ji Kim, Chang Joo Oh, Jae-Han Jeon, Sung Hee Choi, In-Kyu Lee; Diabetes Metab J. 2024;48(3):405-417. Published online February 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0196

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Background
Reactive oxygen species (ROS) and inflammation are reported to have a fundamental role in the pathogenesis of ischemia-reperfusion (IR) injury, a leading cause of acute kidney injury. The present study investigated the role of pyruvate dehydrogenase kinase 4 (PDK4) in ROS production and inflammation following IR injury.
Methods
We used a streptozotocin-induced diabetic C57BL6/J mouse model, which was subjected to IR by clamping both renal pedicles. Cellular apoptosis and inflammatory markers were evaluated in NRK-52E cells and mouse primary tubular cells after hypoxia and reoxygenation using a hypoxia work station.
Results
Following IR injury in diabetic mice, the expression of PDK4, rather than the other PDK isoforms, was induced with a marked increase in pyruvate dehydrogenase E1α (PDHE1α) phosphorylation. This was accompanied by a pronounced ROS activation, as well as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1) production. Notably, sodium dichloroacetate (DCA) attenuated renal IR injury-induced apoptosis which can be attributed to reducing PDK4 expression and PDHE1α phosphorylation levels. DCA or shPdk4 treatment reduced oxidative stress and decreased TNF-α, IL-6, IL-1β, and MCP-1 production after IR or hypoxia-reoxygenation injury.
Conclusion
PDK4 inhibition alleviated renal injury with decreased ROS production and inflammation, supporting a critical role for PDK4 in IR mediated damage. This result indicates another potential target for reno-protection during IR injury; accordingly, the role of PDK4 inhibition needs to be comprehensively elucidated in terms of mitochondrial function during renal IR injury.

Citations

Citations to this article as recorded by

Advancements in early biomarkers of acute kidney injury: from traditional indicators to a paradigm shift in lactate metabolism
Qian Wu, Xinyi Qiu, Hongyu Chen
Annals of Medicine.2026;[Epub] CrossRef
Targeting TFAM K76 acetylation attenuates mitochondrial dysfunction and kidney injury in diabetic kidney disease
Tingting Fu, Shengnan Sun, Zhiye Wang, Fang Zhao, Junhui Zhen, Xingzhao Ji, Fuyuan Xue, Qian Mu, Ying Wang, Yi Liu, Qiang Wan
Cardiovascular Diabetology.2026;[Epub] CrossRef
Hyperoxia-induced fatty liver injury through the AKT-dependent and HIF-2α-independent pathways
Youngmi Song, Sung Ryol Lee, Byung-Wan Lee
American Journal of Physiology-Gastrointestinal and Liver Physiology.2026; 330(4): G498. CrossRef
Transcriptomic identification of PDK4 as a potential target of leonurine to ox-LDL-induced inflammation and lipid accumulation in THP-1 macrophages
Tong Dou, ZhangChi Liu, YiZhuang Yang, Yue Gao, Xu Chen, Juan Wang
Biochemical and Biophysical Research Communications.2026; 820: 153850. CrossRef
Persistent subclinical renal injury in female rats following renal ischemia-reperfusion injury
Desmond Moronge, Hannah Godley, Victor Ayulo, Elisabeth Mellott, Mona Elgazzaz, Gibson Cooper, Riyaz Mohamed, Safia Ogbi, Ellen Gillis, Jessica L. Faulkner, Jennifer C. Sullivan
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Phytomedicine.2025; 140: 156558. CrossRef
Cardiac PDK4 promotes neutrophilic PFKL methylation and drives the innate immune response in diabetic myocardial infarction
Song Yang, Longxin Yan, Lang Chen, Gaijuan Su, Long Yang, Lili Gong, Lihong Liu
Pharmacological Research.2025; 215: 107731. CrossRef
Targeting HDAC3 Suppresses Ferroptosis and Demyelination in White Matter Injury by Restoring PDK4‐Mediated Iron Homeostasis
Ting Xu, Lisha Ye, Wenfeng Li, Fangming Liu, Tianjiao Wei, Wenhui Gu, Lihua Xu, Mingde Fang, Qianqian Luo, Chuanjie Wu, Guohua Wang
CNS Neuroscience & Therapeutics.2025;[Epub] CrossRef
Advances in the therapeutic applications of dichloroacetate as a metabolic regulator: A review
Xiaohuan Wu, Min Shang, Meichuan Li, Yujuan Liu, Han Hu, Ping Zhang, Qiuyi He, Shide Lin
Medicine.2025; 104(36): e44295. CrossRef
Depression, anxiety, and stress impair sperm quality via dysregulation of the mitochondrial PDK–PDC axis
Wang Wang, Wang Qikai, Wang Zilin, Shao Junyan, Jiang Xiaocui, Liu Qi, Chen Shuhui, Zhu Yangyang, Gao Mengjie, Chen Siyi, Cao Jigang, Xiao Min
Reproductive Biology and Endocrinology.2025;[Epub] CrossRef
Integrating Metabolomics LC-HRMS, and Network Pharmacology of Garcinia forbesii King Leaf Extract, Potential for Treatment of Renal Ischemic Reperfusion Injury
Azma Rosida, Nia Kania, Mohammad Rudiansyah, Fujiati Fujiati, Oski Illiandri, Wivina R Devi
Tropical Journal of Natural Product Research.2025;[Epub] CrossRef
Identification and validation of mitochondrial-related genes in intestinal ischemia-reperfusion injury based on WGCNA and machine learning
YiChen Hu, Jie Huang, XiaoLi Min, YuanPei Zhao, JiaHui Wang, HongYuan Liu, KaiWen Shi, WenLiang Li, WeiMing Li
Frontiers in Molecular Biosciences.2025;[Epub] CrossRef
Exploring Renal Pyruvate Metabolism as a Therapeutic Avenue for Diabetic Kidney Injury
Jaemin Lee
Diabetes & Metabolism Journal.2024; 48(3): 385. CrossRef
Cardiovascular Disease and miRNAs: Possible Oxidative Stress-Regulating Roles of miRNAs
Seahyoung Lee
Antioxidants.2024; 13(6): 656. CrossRef
Sodium Phenylbutyrate Attenuates Cisplatin-Induced Acute Kidney Injury Through Inhibition of Pyruvate Dehydrogenase Kinase 4
Chang Joo Oh, Wooyoung Choi, Ha Young Lee, In-Kyu Lee, Min-Ji Kim, Jae-Han Jeon
Biomedicines.2024; 12(12): 2815. CrossRef

Basic Research
CycloZ Improves Hyperglycemia and Lipid Metabolism by Modulating Lysine Acetylation in KK-Ay Mice: Jongsu Jeon, Dohyun Lee, Bobae Kim, Bo-Yoon Park, Chang Joo Oh, Min-Ji Kim, Jae-Han Jeon, In-Kyu Lee, Onyu Park, Seoyeong Baek, Chae Won Lim, Dongryeol Ryu, Sungsoon Fang, Johan Auwerx, Kyong-Tai Kim, Hoe-Yune Jung; Diabetes Metab J. 2023;47(5):653-667. Published online April 26, 2023; DOI: https://doi.org/10.4093/dmj.2022.0244

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Background
CycloZ, a combination of cyclo-His-Pro and zinc, has anti-diabetic activity. However, its exact mode of action remains to be elucidated.
Methods
KK-Ay mice, a type 2 diabetes mellitus (T2DM) model, were administered CycloZ either as a preventive intervention, or as a therapy. Glycemic control was evaluated using the oral glucose tolerance test (OGTT), and glycosylated hemoglobin (HbA1c) levels. Liver and visceral adipose tissues (VATs) were used for histological evaluation, gene expression analysis, and protein expression analysis.
Results
CycloZ administration improved glycemic control in KK-Ay mice in both prophylactic and therapeutic studies. Lysine acetylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, liver kinase B1, and nuclear factor-κB p65 was decreased in the liver and VATs in CycloZ-treated mice. In addition, CycloZ treatment improved mitochondrial function, lipid oxidation, and inflammation in the liver and VATs of mice. CycloZ treatment also increased the level of β-nicotinamide adenine dinucleotide (NAD⁺), which affected the activity of deacetylases, such as sirtuin 1 (Sirt1).
Conclusion
Our findings suggest that the beneficial effects of CycloZ on diabetes and obesity occur through increased NAD⁺ synthesis, which modulates Sirt1 deacetylase activity in the liver and VATs. Given that the mode of action of an NAD+ booster or Sirt1 deacetylase activator is different from that of traditional T2DM drugs, CycloZ would be considered a novel therapeutic option for the treatment of T2DM.

Citations

Citations to this article as recorded by

Beneficial Effects of a Novel Fructose-1,6-Bisphosphatase Inhibitor Cpd96 on Insulin Secretion in Type 2 Diabetes
Kejia Xu, Jiaxuan Zhao, Liran Lei, Quan Liu, Hui Cao, Caina Li, Yi Huan, Xinqian Geng, Lin Zhang, Xi Cao, Ying Yang, Yongzhao Mu, Rongcui Li, Zhufang Shen, Lei Lei, Shuainan Liu
ACS Pharmacology & Translational Science.2026; 9(1): 153. CrossRef
Combined Histidine and Proline Supplementation (HISPRO) Enhances Oxidative and Mitochondrial Function in Skeletal Muscle Through SIRT1-Associated Signaling
Dohyun Lee, Jongsu Jeon, Gyuwon Huh, Seoyeong Baek, Daehun Kim, Hyeon-Ji Kang, Hoyul Lee, In-Kyu Lee, Jae-Han Jeon, Hoe-Yune Jung
Cells.2026; 15(10): 887. CrossRef
Microwave Pretreatment-Induced Significant Nutrient and Metabolite Changes in Sea Cucumber Apostichopus japonicus
Dairong Song, Fang Liu, Airong Jia, Xue Liu, Tingting Cui, Hui Zhang, Miansong Zhang
Marine Drugs.2025; 23(6): 249. CrossRef
Distinct types of protein modifications in diabetic endothelial dysfunction
Qianyou Zhou, Xintong Ge, Zhaojing Chen, Danyi Cao, Yun Chen, Jiahai Shi, Guoliang Meng
Cardiovascular Diabetology.2025;[Epub] CrossRef
Cyclo His‐Pro Attenuates Muscle Degeneration in Murine Myopathy Models
Alessia De Masi, Nadège Zanou, Keno Strotjohann, Dohyun Lee, Tanes I. Lima, Xiaoxu Li, Jongsu Jeon, Nicolas Place, Hoe‐Yune Jung, Johan Auwerx
Advanced Science.2024;[Epub] CrossRef
CycloZ Suppresses TLR4-Driven Inflammation to Reduce Asthma-Like Responses in HDM-Exposed Mouse Models
Dohyun Lee, Jongsu Jeon, Seoyeong Baek, Onyu Park, Ah-Ram Kim, Myoung-Sool Do, Hoe-Yune Jung
Cells.2024; 13(23): 2034. CrossRef
Cyclic Peptides as Protein Kinase Modulators and Their Involvement in the Treatment of Diverse Human Diseases
Lorena Martínez-Alcantar, Laura Hernández-Padilla, Alma Laura Díaz-Pérez, Lizbeth Guadalupe Villalón-Magallán, Mayra Xóchitl Durán-Maldonado, César Díaz-Pérez, Marlene E. Campos-Morales, Citlali Figueroa-Guzmán, Jesús Campos-García
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