Diabetes & Metabolism Journal

Original Articles

Pharmacotherapy
D2Rs Agonist Ropinirole Cooperates with Metformin to Modulate Thermogenesis and Ameliorate Obesity-Related Metabolic Disorders in Mice: Bangrui Huang, Daowei Liu, Fakun Jiang, Zihui Wang, Chuanjun Mao, Qian Lu, Tao Chen, Chun Xie, Wenli Chen, Qian Wang, Wenyong Xiong; Received April 14, 2025 Accepted October 4, 2025 Published online February 4, 2026; DOI: https://doi.org/10.4093/dmj.2025.0335 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Metabolic disorders represent a significant challenge to human health, primarily due to their widespread prevalence and the limited availability of alternative pharmacological interventions. Drug repurposing offers a promising and expedited strategy to address these conditions.
Methods
To elucidate the efficacy and underlying mechanism of the combination of metformin with ropinirole on anti-obesity and obesity-related metabolic disorders.
Results
The results indicate that the combination treatment led to a significant reduction in body weight and improvements in hyperglycemia, dyslipidemia, and insulin resistance. These enhancements, along with increased energy expenditure, were significantly greater than those achieved with either drug alone. Additionally, we observed the browning of inguinal white adipose tissue (iWAT) and alterations of the whitened-brown adipose tissue (BAT), along with substantial increases in mitochondrial function-related proteins. However, the drug combination did not exhibit any enhanced effect on cell thermogenesis and these proteins in vitro, whereas combination of norepinephrine and metformin-induced an additive upregulation of mitochondrial function-related proteins. Furthermore, pharmacological blockade of the β3 adrenergic receptor inhibited the energy expenditure induced by the combination treatment, etc.
Conclusion
Our study underscores the combination of metformin and ropinirole-induced an amplified effectiveness in treating obesity-related metabolic disorders is dependent on the dopamine-control sympathetic nerve activity, and metformin acts directly on BAT and iWAT to improve mitochondrial function, which offering a new perspective for future clinical co-treatment of metabolic disorders with these two drugs.

Complications
BDH1 Protects against Diabetic Cardiomyopathy by Improving Mitochondrial Function and Suppressing Cardiomyocyte Apoptosis Via Activation of the AKT/GSK3β Pathway: Yan Wang, Yanan Cheng, Jianbo Wu, Yu Zhao, Di Wang, Longyan Yang, Dong Zhao; Received March 26, 2025 Accepted September 8, 2025 Published online January 19, 2026; DOI: https://doi.org/10.4093/dmj.2025.0257 [Epub ahead of print]

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Diabetic cardiomyopathy (DCM) is the main cause of heart failure in diabetes patients with no effective therapies currently available. A deeper understanding of the mechanisms underlying DCM is essential for identifying novel therapeutic targets.
Methods
DCM model was established in C57BL/6J mice by administering multiple low-dose intraperitoneal injections of streptozotocin (STZ) in combination with a high-fat diet (HFD). Proteomic profiling was conducted on cardiac tissues from control and DCM mice to identify differentially expressed proteins. The expression of β-hydroxybutyrate dehydrogenase 1 (BDH1, also known as 3-hydroxybutyrate dehydrogenase) in cardiac tissues and cardiomyocyte were determined by immunoblot and quantitative polymerase chain reaction. The function and mechanism of BDH1 in DCM were investigated using a cardiac-specific BDH1-overexpressing mouse model, combined with cardiomyocyte cell lines with either BDH1 overexpression or knockdown.
Results
BDH1 was markedly downregulated in cardiac tissues of DCM mice, as well as in cardiomyocytes treated with high glucose and palmitic acid (HGPA). Cardiac-specific overexpression of BDH1 markedly improved cardiac dysfunction and myocardial fibrosis in DCM mice. In vitro, BDH1 overexpression attenuated mitochondrial damage and inhibited apoptosis in cardiomyocytes induced by HGPA. Conversely, BDH1 knockdown exacerbated these pathological changes under HGPA conditions. Transcriptome analysis linked BDH1 expression to the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) pathway, and we confirmed that BDH1 overexpression reversed diabetes-induced inhibition of the AKT/glycogen synthase kinase 3β (GSK3β) pathway. The protective effects of BDH1 on mitochondrial function and cardiomyocytes apoptosis were abolished following treatment with AKT inhibitor (AKTi). Cardiac-specific overexpression of BDH1 markedly decreased β-hydroxybutyric acid (BHB, the predominant ketone body) levels in cardiac tissues of DCM mice. Elevated BHB levels suppressed AKT activation in cardiomyocytes, while BDH1 overexpression effectively restored AKT/GSK3β pathway activity and ameliorated BHB-induced mitochondrial dysfunction and cardiomyocytes apoptosis.
Conclusion
Our study demonstrates that BDH1 plays a protective role in DCM by regulating BHB level and activating the AKT/GSK3β pathway, thereby mitigating mitochondrial damage and cardiomyocyte apoptosis. BDH1 may be a promising therapeutic target for DCM.

Complications
Targeting SLC25A33 Suppresses Vascular Smooth Muscle Cell Proliferation and Migration by Reducing Cytosolic mtDNA Levels: Implications for Occlusive Vascular Diseases: Daehoon Kim, Jieun Shin, Yeon-Kyung Choi, You Mie Lee, Keun-Gyu Park, Hyang Sook Kim, Jun-Kyu Byun; Diabetes Metab J. 2026;50(1):139-152. Published online July 30, 2025; DOI: https://doi.org/10.4093/dmj.2024.0632

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Abstract PDF Supplementary Material PubReader ePub: Background
Vascular smooth muscle cells (VSMCs) play a crucial role in the development of occlusive vascular diseases through abnormal proliferation and migration. This pathological behavior is closely associated with mitochondrial reactive oxygen species (ROS)-mediated mitochondrial DNA (mtDNA) damage. The mitochondrial carrier protein solute carrier family 25 member 33 (SLC25A33), essential for nucleoside transport, is integral to mtDNA production. This study aimed to investigate the effects of SLC25A33 inhibition on the proliferation and migration of VSMCs, as well as its impact on neointima formation.
Methods
VSMCs were isolated from the thoracic aorta of 4-week-old Sprague-Dawley rats. The effects of small interfering RNAinduced silencing of SLC25A33 mRNA on platelet-derived growth factor (PDGF)-induced proliferation and migration of VSMCs were analyzed. The in vivo effects of targeting the SLC25A33 gene on neointima formation were evaluated using a murine carotid artery ligation model by perivascularly applying Lenti-shSLC25A33 with Pluronic F-127 gel.
Results
First, we observed an upregulation of the SLC25A33 protein in the carotid artery ligation-induced neointima in mice. Silencing of SLC25A33 suppressed the PDGF-stimulated proliferation and migration of VSMCs and cell cycle progression. Knockdown of SLC25A33 inhibited PDGF-induced production of mtDNA and ROS, consequently inactivating the cyclic GMP-AMP synthesis (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1)-nuclear factor kappa B (NF-κB) pathway. Furthermore, the downregulation of SLC25A33 reduced carotid artery ligation-induced neointima in mice.
Conclusion
This study suggests that targeting SLC25A33 in VSMCs could be a novel therapeutic strategy to prevent occlusive vascular diseases.

Basic Research
PDZD8 Augments Endoplasmic Reticulum-Mitochondria Contact and Regulates Ca²⁺ Dynamics and Cypd Expression to Induce Pancreatic β-Cell Death during Diabetes: Yongxin Liu, Yongqing Wei, Xiaolong Jin, Hongyu Cai, Qianqian Chen, Xiujuan Zhang; Diabetes Metab J. 2024;48(6):1058-1072. Published online July 29, 2024; DOI: https://doi.org/10.4093/dmj.2023.0275

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Abstract PDF Supplementary Material PubReader ePub

Background
Diabetes mellitus (DM) is a chronic metabolic disease that poses serious threats to human physical and mental health worldwide. The PDZ domain-containing 8 (PDZD8) protein mediates mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) formation in mammals. We explored the role of PDZD8 in DM and investigated its potential mechanism of action.
Methods
High-fat diet (HFD)- and streptozotocin-induced mouse DM and palmitic acid (PA)-induced insulin 1 (INS-1) cell models were constructed. PDZD8 expression was detected using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. MAM formation, interactions between voltage-dependent anion-selective channel 1 (VDAC1) and inositol 1,4,5-triphosphate receptor type 1 (IP3R1), pancreatic β-cell apoptosis and proliferation were detected using transmission electron microscopy (TEM), proximity ligation assay (PLA), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunofluorescence staining, and Western blotting. The mitochondrial membrane potential, cell apoptosis, cytotoxicity, and subcellular Ca²⁺ localization in INS-1 cells were detected using a JC-1 probe, flow cytometry, and an lactate dehydrogenase kit.
Results
PDZD8 expression was up-regulated in the islets of HFD mice and PA-treated pancreatic β-cells. PDZD8 knockdown markedly shortened MAM perimeter, suppressed the expression of MAM-related proteins IP3R1, glucose-regulated protein 75 (GRP75), and VDAC1, inhibited the interaction between VDAC1 and IP3R1, alleviated mitochondrial dysfunction and ER stress, reduced the expression of ER stress-related proteins, and decreased apoptosis while increased proliferation of pancreatic β-cells. Additionally, PDZD8 knockdown alleviated Ca²⁺ flow into the mitochondria and decreased cyclophilin D (Cypd) expression. Cypd overexpression alleviated the promoting effect of PDZD8 knockdown on the apoptosis of β-cells.
Conclusion
PDZD8 knockdown inhibited pancreatic β-cell death in DM by alleviated ER-mitochondria contact and the flow of Ca²⁺ into the mitochondria.

Citations

Citations to this article as recorded by

Aerobic Training Modulates the Expression of Components of the mPTP Through the Reduction of Oxidative Stress in the Soleus Muscle of Streptozotocin-Induced Diabetic Rats
Luis Alberto Sánchez-Briones, Sarai Sánchez-Duarte, Sergio Márquez-Gamiño, Karla Susana Vera-Delgado, Montserrat Guadalupe Vera-Delgado, Rocío Montoya-Pérez, Cipriana Caudillo-Cisneros, Elizabeth Sánchez-Duarte
Diabetology.2026; 7(1): 18. CrossRef
The spatiotemporal dynamics of MAMs: mechanisms, pathologies, and therapeutic rewiring
Dongxue Xu, Yinye Huang, Xiaoyu Zhang, Benzheng Liu, Mingying Wang, Yiming Li, Zhiyong Peng
Cellular & Molecular Biology Letters.2026;[Epub] CrossRef
Cornuside as a promising therapeutic agent for diabetic kidney disease: Targeting regulation of Ca2+ disorder-mediated renal tubular epithelial cells apoptosis
Gai Gao, Xuan Su, Shuyan Liu, Pan Wang, Jenny Jie Chen, Tongxiang Liu, Jiangyan Xu, Zhenqiang Zhang, Xiaowei Zhang, Zhishen Xie
International Immunopharmacology.2025; 149: 114190. CrossRef
Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice
Andreea D. Pantiru, Stijn Van de Sompele, Clemence Ligneul, Camille Chatelain, Christophe Barrea, Jason P. Lerch, Beatrice M. Filippi, Serpil Alkan, Elfride De Baere, Jamie Johnston, Steven J. Clapcote
Molecular Autism.2025;[Epub] CrossRef
Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering
Koki Nakamura, Saeko Aoyama-Ishiwatari, Takahiro Nagao, Mohammadreza Paaran, Christopher J. Obara, Yui Sakurai-Saito, Jake Johnston, Yudan Du, Shogo Suga, Masafumi Tsuboi, Makoto Nakakido, Kouhei Tsumoto, Yusuke Kishi, Yukiko Gotoh, Chulhwan Kwak, Hyun-Wo
Nature Communications.2025;[Epub] CrossRef
Mitochondria‐Associated Endoplasmic Reticulum Membranes in Human Health and Diseases
Yong Liu, Zi‐Hui Mao, Junwen Huang, Hui Wang, Xiao Zhang, Xin Zhou, Yue Xu, Shaokang Pan, Dongwei Liu, Zhangsuo Liu, Qi Feng
MedComm.2025;[Epub] CrossRef
Inhibition of STING-induced mitochondrial Drp1/N-GSDMD-mediated MtDNA release alleviates Sepsis-induced lung injury
Shishi Zou, Yifan Zuo, Yukai Chen, Tianyu Zhang, Tinglv Fu, Guorui Li, Rui Xiong, Bohao Liu, Yong Hu, Zhaoyu Hu, Chunguang Miao, Xiaojing Wu, Ning Li, Qing Geng
Cellular and Molecular Life Sciences.2025;[Epub] CrossRef
Tanshinone IIA ameliorates pancreatic injury in type 2 diabetic mice by modulating inflammation and endoplasmic reticulum stress via the IL-6/JAK2/STAT3 pathway
Yingfeng Li, Desheng Wang, Yuhang Liu, Chenyang Liu, Meixi Chen, Jingqi Li, Zunqiu Wu, Ning Wu
Functional & Integrative Genomics.2025;[Epub] CrossRef
Mitochondrial integrations in pancreatic acinar cells: inter-organelle interaction as a key factor in the pathogenesis of acute pancreatitis
S.M. Chooklin, S.S. Chuklin, R.V. Barylyak
GASTROENTEROLOGY.2025; 59(4): 289. CrossRef

Basic Research
DGAT2 Plays a Crucial Role to Control ESRRA-PROX1 Transcriptional Network to Maintain Hepatic Mitochondrial Sustainability: Yoseob Lee, Yeseong Hwang, Minki Kim, Hyeonuk Jeon, Seyeon Joo, Sungsoon Fang, Jae-Woo Kim; Diabetes Metab J. 2024;48(5):901-914. Published online April 22, 2024; DOI: https://doi.org/10.4093/dmj.2023.0368

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Abstract PDF Supplementary Material PubReader ePub

Background
Diacylglycerol O-acyltransferase 2 (DGAT2) synthesizes triacylglycerol (TG) from diacylglycerol; therefore, DGAT2 is considered as a therapeutic target for steatosis. However, the consequence of inhibiting DGAT2 is not fully investigated due to side effects including lethality and lipotoxicity. In this article, we observed the role of DGAT2 in hepatocarcinoma.
Methods
The role of DGAT2 is analyzed via loss-of-function assay. DGAT2 knockdown (KD) and inhibitor treatment on HepG2 cell line was analyzed. Cumulative analysis of cell metabolism with bioinformatic data were assessed, and further compared with different cohorts of liver cancer patients and non-alcoholic fatty liver disease (NAFLD) patients to elucidate how DGAT2 is regulating cancer metabolism.
Results
Mitochondrial function is suppressed in DGAT2 KD HepG2 cell along with the decreased lipid droplets. In the aspect of the cancer, DGAT2 KD upregulates cell proliferation. Analyzing transcriptome of NAFLD and hepatocellular carcinoma (HCC) patients highlights negatively correlating expression patterns of 73 lipid-associated genes including DGAT2. Cancer patients with the lower DGAT2 expression face lower survival rate. DGAT2 KD cell and patients’ transcriptome show downregulation in estrogen- related receptor alpha (ESRRA) via integrated system for motif activity response analysis (ISMARA), with increased dimerization with corepressor prospero homeobox 1 (PROX1).
Conclusion
DGAT2 sustains the stability of mitochondria in hepatoma via suppressing ESRRA-PROX1 transcriptional network and hinders HCC from shifting towards glycolytic metabolism, which lowers cell proliferation.

Citations

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Identification of the biomarkers associated with lipid metabolism and endoplasmic reticulum stress in pediatric sepsis through bioinformatics analysis and quantitative reverse transcriptase PCR (qRT-PCR) assay
Baoju Shan, Jiaoyang Cao, Ting Yang
European Journal of Medical Research.2026;[Epub] CrossRef
PLD2 is a marker for MASLD-HCC with early-stage fibrosis: revealed by lipidomic and gene expression analysis
Jihan Sun, Fatima Dahboul, Estelle Pujos-Guillot, Mélanie Petera, Emeline Chu-Van, Benoit Colsch, Delphine Weil, Vincent Di Martino, Aicha Demidem, Armando Abergel
Metabolomics.2025;[Epub] CrossRef

Brief Report

Genetics
Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea: Eun Hoo Rho, Sang Ik Baek, Heerah Lee, Moon-Woo Seong, Jong-Hee Chae, Kyong Soo Park, Soo Heon Kwak; Diabetes Metab J. 2024;48(3):482-486. Published online February 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0078

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Abstract PDF Supplementary Material PubReader ePub

Maternally inherited diabetes and deafness (MIDD) is a rare mitochondrial disorder primarily resulting from m.3243A>G mutation. The clinical characteristics of MIDD exhibit significant heterogeneity. Our study aims to delineate these characteristics and determine the potential correlation with m.3243A>G heteroplasmy levels. This retrospective, descriptive study encompassed patients with confirmed m.3243A>G mutation and diabetes mellitus at Seoul National University Hospital. Our cohort comprises 40 patients with MIDD, with a mean age at study enrollment of 33.3±12.9 years and an average % of heteroplasmy of 30.0%± 14.6% in the peripheral blood. The most prevalent comorbidity was hearing loss (90%), followed by albuminuria (61%), seizure (38%), and stroke (33%). We observed a significant negative correlation between % of heteroplasmy and age at diabetes diagnosis. These clinical features can aid in the suspicion of MIDD and further consideration of genetic testing for m.3243A>G mutation.

Citations

Citations to this article as recorded by

Approach to the Patient: Mitochondrial Diabetes: Contemporary Cases and a Precision Medicine Approach
Kaylee R Oppenheimer, Nava T Himelhoch, Michael E McCullough, Tiana L Bowden, Balamurugan Kandasamy, Lisa R Letourneau-Freiberg, Rochelle N Naylor, Siri Atma W Greeley, Louis H Philipson
The Journal of Clinical Endocrinology & Metabolism.2026; 111(4): 1175. CrossRef
Before diagnosing immunological cerebellitis in an m.3243A>G carrier, a cerebellar stroke-like lesion should be ruled out
Josef Finsterer
Rinsho Shinkeigaku.2026; 66(3): 190. CrossRef
Monogenic diabetes: the role of mitochondrial dysfunction and endoplasmic reticulum stress
Elif Ozsu
Frontiers in Clinical Diabetes and Healthcare.2025;[Epub] CrossRef
Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea (Diabetes Metab J 2024;48:482-6)
Eun Hoo Rho, Soo Heon Kwak
Diabetes & Metabolism Journal.2024; 48(4): 818. CrossRef
MIDD Patients Should Not Be Confused with MELAS Patients, Even Though Both Carry the m.3243A>G Variant
Josef Finsterer, Sounira Mehri
Diabetes & Metabolism Journal.2024; 48(4): 816. CrossRef
Diagnosis and Management of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Syndrome
Ji-Hoon Na, Young-Mock Lee
Biomolecules.2024; 14(12): 1524. CrossRef

Reviews

Basic Research
Mitochondrial Stress and Mitokines: Therapeutic Perspectives for the Treatment of Metabolic Diseases: Benyuan Zhang, Joon Young Chang, Min Hee Lee, Sang-Hyeon Ju, Hyon-Seung Yi, Minho Shong; Diabetes Metab J. 2024;48(1):1-18. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2023.0115

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