Diabetes & Metabolism Journal

Original Articles

Basic and Translational Research
Targeting PGC-1α by miRNA-374 Simultaneously Improve β-Cell Dysfunction and Suppress Hepatic Glucose Overproduction: Ji-Won Kim, Joonyub Lee, Young-Hye You, Chan-Hee Oh, Heon-Seok Park, Eun Young Lee, Seung-Hwan Lee, Seung-Hyun Ko, Ji-Ho Park, Kun-Ho Yoon; Diabetes Metab J. 2026;50(3):535-551. Published online November 3, 2025; DOI: https://doi.org/10.4093/dmj.2025.0287

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Background
In this study, we aimed to validate the potential of miR-374 in ameliorating hyperglycemia by regulating peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α) expression in pancreatic islets and liver.
Methods
To identify miRNAs targeting PGC-1α, we performed miRNA chip analysis in rat islets under hyperglycemic and euglycemic conditions. Luciferase reporter assay was performed to identify miR binding sites in the 3’-untranslated region (3’ UTR) of PGC-1α. In db/db mice, miRNA-encapsulated adenoviruses were administered and intraperitoneal glucose tolerance test and glucose stimulated insulin secretion tests were performed. For enhanced delivery to β-cells, we developed exendin-4 (Ex-4) coated cationic lipoparticles (CCLs) encapsulating miRNAs. The therapeutic potential of Ex-4-CCL-miRNA was further evaluated in insulin-producing cells derived from induced pluripotent stem cells.
Results
By analyzing miRNA expression in primary rat islets exposed under hyperglycemic environment, we identified miR-374 as a potential target. In vitro experiments confirmed that miR-374 significantly suppressed PGC-1α expression in β-cells and hepatocytes by binding to its 3’-UTR. In vivo experiments using adenovirus-mediated miR-374 (Ad-miR-374) delivering directly to the pancreas and liver of db/db mice demonstrated improved glycemic control, enhanced insulin secretion, and downregulated hepatic gluconeogenesis-related genes (G6Pase, Pepck, PC). To enhance the clinical applicability of miR-374, we developed Ex-4-CCLs. Ex-4-CCL-miR-374 successfully alleviated hyperglycemia, restored pancreatic islet function, and decreased gluconeogenesis gene expression in db/db mice. Furthermore, Ex-4-CCL-miR-374 improved insulin secretory function in glucotoxicity-exposed human induced pluripotent stem cell-derived insulin producing cells.
Conclusion
Based on these findings, we propose that Ex-4-CCL-miR-374 as a promising therapeutic approach to reverse β-cell dysfunction and improve hepatic insulin resistance in type 2 diabetes mellitus.

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β‐cell recovery revisited: Is prediabetes remission driven by insulin sensitivity or β‐cell function?
Joonyub Lee, Kun‐Ho Yoon
Journal of Diabetes Investigation.2026; 17(5): 716. CrossRef

Pathophysiology
Deficiency of ASGR1 Alleviates Diet-Induced Systemic Insulin Resistance via Improved Hepatic Insulin Sensitivity: Xiaorui Yu, Jiawang Tao, Yuhang Wu, Yan Chen, Penghui Li, Fan Yang, Miaoxiu Tang, Abdul Sammad, Yu Tao, Yingying Xu, Yin-Xiong Li; Diabetes Metab J. 2024;48(4):802-815. Published online February 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0124

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Background
Insulin resistance (IR) is the key pathological basis of many metabolic disorders. Lack of asialoglycoprotein receptor 1 (ASGR1) decreased the serum lipid levels and reduced the risk of coronary artery disease. However, whether ASGR1 also participates in the regulatory network of insulin sensitivity and glucose metabolism remains unknown.
Methods
The constructed ASGR1 knockout mice and ASGR1^-/- HepG2 cell lines were used to establish the animal model of metabolic syndrome and the IR cell model by high-fat diet (HFD) or drug induction, respectively. Then we evaluated the glucose metabolism and insulin signaling in vivo and in vitro.
Results
ASGR1 deficiency ameliorated systemic IR in mice fed with HFD, evidenced by improved insulin intolerance, serum insulin, and homeostasis model assessment of IR index, mainly contributed from increased insulin signaling in the liver, but not in muscle or adipose tissues. Meanwhile, the insulin signal transduction was significantly enhanced in ASGR1^-/- HepG2 cells. By transcriptome analyses and comparison, those differentially expressed genes between ASGR1 null and wild type were enriched in the insulin signal pathway, particularly in phosphoinositide 3-kinase-AKT signaling. Notably, ASGR1 deficiency significantly reduced hepatic gluconeogenesis and glycogenolysis.
Conclusion
The ASGR1 deficiency was consequentially linked with improved hepatic insulin sensitivity under metabolic stress, hepatic IR was the core factor of systemic IR, and overcoming hepatic IR significantly relieved the systemic IR. It suggests that ASGR1 is a potential intervention target for improving systemic IR in metabolic disorders.

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Increased Asialoglycoprotein Receptor 1 Level in Granulosa Cell as a Potential Biomarker for Polycystic Ovary Syndrome
Xitong Liu, Rongxia Xie, Yang Cai, Hui Lan, Jing Mu, Chen Zhang, Bo Li
Reproductive Sciences.2026; 33(1): 174. CrossRef
Proteomic Markers of Dietary Patterns, CKD Progression, and Mortality in the CRIC Study
Valerie K. Sullivan, Jingsha Chen, Lawrence J. Appel, Sarah Schrauben, Ana C. Ricardo, Panduranga Rao, Mirela Dobre, Nishigandha Pradhan, Jing Chen, Jiang He, Hernan Rincon-Choles, Paul L. Kimmel, Casey M. Rebholz
Clinical Journal of the American Society of Nephrology.2026; 21(4): 553. CrossRef
Serum soluble ASGR1 concentration is elevated in patients with metabolic dysfunction-associated steatotic liver disease and is associated with adiponectin
Jing-Ming Wang, Li-Yan Jiang, Yu-Ting Deng, Jiao-Yang Li, Heng Sun, Li Ran, Xinhua Xiao
BMJ Open Diabetes Research & Care.2026; 14(1): e005638. CrossRef
ASGR1 exacerbates MASLD by inducing hepatocyte senescence via lysosomal dysfunction and HIF-1α stabilization
Chen-Yu Zhang, Jie Ding, Yi-Jia Sun, Wen-Jing Zhong, Nan-Si-Yu Yang, Pei-Ze Li, Jia-Hui Zheng, Jin-Tong Yang, Li-Ying Liang, Yong Zhou, Si-Yuan Tang, Xiao-Ting Huang
Metabolism.2026; 184: 156747. CrossRef
The asialoglycoprotein receptor 1 (ASGR1): emerging new roles in health and disease
Demeke Geremew, Joanne T. M. Tan, Peter J. Psaltis, Christina A. Bursill
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Association Analysis of the Circulating Proteome With Sarcopenia‐Related Traits Reveals Potential Drug Targets for Sarcopenia
Simin Wen, Siqi Xu, Xizeng Zong, Shifeng Wen, Wende Xiao, Weipeng Zheng, Han Cen, Zhaohua Zhu, Jingyu Xie, Yan Zhang, Changhai Ding, Guangfeng Ruan
Journal of Cachexia, Sarcopenia and Muscle.2025;[Epub] CrossRef
Serum Soluble Asialoglycoprotein Receptor 1: A Potential Predictor Marker Linked to Type 2 Diabetes Mellitus, Demonstrating Positive Correlation With High Sensitive C-Reactive Protein
Haifeng Zhu, Ziyi Zhong, Gaonian Zhao, Yuan Cao, Wei Liu, Yawen Guo, Jing Jin
Diabetes, Metabolic Syndrome and Obesity.2025; Volume 18: 663. CrossRef
Cross-sectional, interventional, and causal investigation of insulin sensitivity using plasma proteomics in diverse populations
Pik Fang Kho, Neil Wary, Daniela Zanetti, Fahim Abbasi, Joshua W. Knowles, Daniel J. Panyard, Katie T. Watson, Laurel Stell, Laura C. Lazzeroni, Stefan Gustafsson, Lars Lind, John R. Petrie, Themistocles L. Assimes
Metabolism.2025; 169: 156263. CrossRef
Causal Relationship Between Serum Zinc Levels and Diabetic Kidney Disease (DKD): A Plasma Proteomics Mediation Study
Chunbo Zhao, Tingting Pan, Wei Liu, Fanqian Cheng, Xiaoxuan Zhao, Shuxin Yu, Yi Yang, Ran Zhang, Weixia Sun
Biological Trace Element Research.2025; 204(3): 1768. CrossRef
Triglyceride-glucose index and triglyceride-to-high-density lipoprotein cholesterol ratio as novel predictors of acute kidney injury: an analysis of the UK biobank
Fangfang Zhou, Yuanyuan Wang, Youjun Xu, Lailiang Wang, Jinxia Ge, Qun Luo, Hongpeng Sun
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Experimental cell models of insulin resistance: overview and appraisal
Ying Yang, Ting-ting Wang, Hu-ai Xie, Ping Ping Hu, Pan Li
Frontiers in Endocrinology.2024;[Epub] CrossRef

Basic Research
DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion in Diabetic Mice: Youjin Kim, Si Woo Lee, Hyejin Wang, Ryeong-Hyeon Kim, Hyun Ki Park, Hangkyu Lee, Eun Seok Kang; Diabetes Metab J. 2022;46(2):337-348. Published online January 21, 2022; DOI: https://doi.org/10.4093/dmj.2021.0056

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Background
We investigated the antidiabetic effects of DA-1241, a novel G protein-coupled receptor (GPR) 119 agonist, in vitro and in vivo.
Methods
DA-1241 was administrated to high-fat diet (HFD)-fed C57BL/6J mice for 12 weeks after hyperglycaemia developed. Oral/intraperitoneal glucose tolerance test and insulin tolerance test were performed. Serum insulin and glucagon-like peptide-1 (GLP-1) levels were measured during oral glucose tolerance test. Insulinoma cell line (INS-1E) cells and mouse islets were used to find whether DA-1241 directly stimulate insulin secretion in beta cell. HepG2 cells were used to evaluate the gluconeogenesis and autophagic process. Autophagic flux was evaluated by transfecting microtubule-associated protein 1 light chain 3-fused to green fluorescent protein and monomeric red fluorescent (mRFP-GFP-LC3) expression vector to HepG2 cells.
Results
Although DA-1241 treatment did not affect body weight gain and amount of food intake, fasting blood glucose level decreased along with increase in GLP-1 level. DA-1241 improved only oral glucose tolerance test and showed no effect in intraperitoneal glucose tolerance test. No significant effect was observed in insulin tolerance test. DA-1241 did not increase insulin secretion in INS-1E cell and mouse islets. DA-1241 reduced triglyceride content in the liver thereby improved fatty liver. Additionally, DA-1241 reduced gluconeogenic enzyme expression in HepG2 cells and mouse liver. DA-1241 reduced autophagic flow in HepG2 cells.
Conclusion
These findings suggested that DA-1241 augmented glucose-dependent insulin release via stimulation of GLP-1 secretion, and reduced hepatic gluconeogenesis, which might be associated with autophagic blockage, leading to improved glycaemic control.

Citations

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High‐Protein Diet Exacerbates Insulin Resistance via the JNK/IKKβ‐IRS‐1 Pathway
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Human milk fat substitutes improve obesity-related NAFLD by enriching LPC 18:2 to activate hepatic GPR119–AMPK signaling
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Review

Others
A Journey to Understand Glucose Homeostasis: Starting from Rat Glucose Transporter Type 2 Promoter Cloning to Hyperglycemia: Yong Ho Ahn; Diabetes Metab J. 2018;42(6):465-471. Published online November 2, 2018; DOI: https://doi.org/10.4093/dmj.2018.0116

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My professional journey to understand the glucose homeostasis began in the 1990s, starting from cloning of the promoter region of glucose transporter type 2 (GLUT2) gene that led us to establish research foundation of my group. When I was a graduate student, I simply thought that hyperglycemia, a typical clinical manifestation of type 2 diabetes mellitus (T2DM), could be caused by a defect in the glucose transport system in the body. Thus, if a molecular mechanism controlling glucose transport system could be understood, treatment of T2DM could be possible. In the early 70s, hyperglycemia was thought to develop primarily due to a defect in the muscle and adipose tissue; thus, muscle/adipose tissue type glucose transporter (GLUT4) became a major research interest in the diabetology. However, glucose utilization occurs not only in muscle/adipose tissue but also in liver and brain. Thus, I was interested in the hepatic glucose transport system, where glucose storage and release are the most actively occurring.

Citations

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Missense mutation of ISL1 (E283D) is associated with the development of type 2 diabetes
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Original Article

AMPK Activator AICAR Inhibits Hepatic Gluconeogenesis and Fatty Acid Oxidation.: Jin Yob Kim, Eun Hee Koh, Woo Je Lee, Seong Min Han, Ji Young Youn, Hye Sun Park, Hyun Sik Kim, Min Seon Kim, Joong Yeol Park, Ki Up Lee; Korean Diabetes J. 2005;29(1):6-14. Published online January 1, 2005

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Abstract PDF: BACKGROUND
Recent studies have demonstrated that adiponectin and metformin activate AMPK in the liver, and adiponectin and metformin stimulate fatty acid oxidation while inhibiting glucose production in liver. These results are in contrast to previous studies that have demonstrated that increased fatty acid oxidation in the liver is associated with increased gluconeogenesis. The present study was undertaken to reinvestigate the effects of AMPK activation by AICAR on hepatic fatty acid oxidation and gluconeogenesis. METHODS: HePG2 cells were treated with various concentrations of AICAR, and then the fatty acid oxidation and gluconeogenesis of the cells were determined. To investigate the in vivo effect of AICAR, Sprague-Dawely rats were infused with AICAR (bolus, 40 mg/g; constant, 7.5 mg/g/min-1) for 90min. RESULTS: Incubation of the HePG2 cells with higher concentrations (=1 mM) of AICAR increased fatty acid oxidation and gluconeogenesis. On the other hand, incubation of HePG2 cells with lower concentrations (0.05 and 0.1 mM) of AICAR decreased fatty acid oxidation and gluconeogenesis. Consistent with this in vitro data, the intravenous administration of AICAR to rats lowered their plasma glucose concentration and inhibited hepatic gluconeogenesis. Fatty acid oxidation in the liver tissue was significantly decreased by the administration of AICAR. CONCLUSION: The present study has demonstrated that AICAR decreased gluconeo-genesis in the liver. In contrast to previous studies, AICAR profoundly decreased hepatic fatty acid oxidation in rats and also in cultured hepatocytes

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