Diabetes & Metabolism Journal

Original Articles

Pathophysiology
Enavogliflozin, an SGLT2 Inhibitor, Improves Nonalcoholic Steatohepatitis Induced by High-Fat, High-Cholesterol Diet: Phuc Thi Minh Pham, Giang Nguyen, So Young Park, Thuy Linh Lai, Dae-Hee Choi, Jeana Hong, Seon Mee Kang, Eun-Hee Cho; Received May 21, 2024 Accepted December 26, 2024 Published online June 16, 2025; DOI: https://doi.org/10.4093/dmj.2024.0259 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Nonalcoholic fatty liver disease, a progressive condition caused by the accumulation of fat in the liver, begins with simple steatosis and can potentially progress to metabolic dysfunction-associated steatohepatitis (MASH) in the presence of inflammation and fibrosis, ultimately leading to cirrhosis or hepatocellular carcinoma. Increasing evidence indicates that sodiumglucose cotransporter 2 (SGLT2) inhibitors effectively alleviate MASH in mouse models. However, there is a lack of research on the effects of enavogliflozin on liver disease. In the present study, we investigated the effects of SGLT2 inhibitors on MASH induced by a high-fat, high-cholesterol (HFHC) diet in mice.
Methods
Male C57BL/6 mice were fed a normal chow diet, HFHC diet, or HFHC diet with enavogliflozin for 12 weeks. LX-2 and HepG2 cells were treated with enavogliflozin in the presence of various pathological stimuli.
Results
The HFHC diet induced excessive hepatic lipid accumulation, inflammation, and severe fibrosis. Administration of enavogliflozin not only ameliorated hepatic steatosis and fibrotic conditions but also suppressed the production of inflammatory cytokines. Positive outcomes were also observed in in vitro experiments, where enavogliflozin demonstrated the ability to impede the activation of hepatic stellate cells and alleviate lipid accumulation in hepatocytes. The potential pathway through which enavogliflozin attenuated liver fibrosis development may be associated with the transforming growth factor β1/Smad signaling pathway.
Conclusion
Our results suggest that enavogliflozin is effective in a mouse model of MASH by attenuating hepatic steatosis, suppressing inflammation, and improving liver fibrosis.

Others
Assessing Nutritional Factors for Metabolic Dysfunction-Associated Steatotic Liver Disease via Diverse Statistical Tools: Yea-Chan Lee, Hye Sun Lee, Soyoung Jeon, Yae-Ji Lee, Yu-Jin Kwon, Ji-Won Lee; Received January 9, 2025 Accepted March 19, 2025 Published online June 9, 2025; DOI: https://doi.org/10.4093/dmj.2025.0026 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Lifestyle modifications are critical in addressing metabolic dysfunction-associated steatotic liver disease (MASLD); however, the specific macronutrients that most significantly influence the disease’s progression are uncertain. In this study, we aimed to explore the role of carbohydrate, fat, and protein intake in MASLD development using decision trees, random forest models, and cluster analysis.
Methods
Participants (n=3,951) from the Korean Genome and Epidemiology Study were included. We used the classification and regression tree analysis to classify participants into subgroups based on variables associated with the incidence of new-onset MASLD. Random forest analyses were used to assess the relative importance of each variable. Participants were grouped into homogeneous clusters based on carbohydrate, protein, fat, and total caloric intake using hierarchical cluster analysis. Subsequently, we used the Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for MASLD risk across the clusters.
Results
Carbohydrate intake was identified as the most significant predictor of new-onset MASLD, followed by fat, protein, and total caloric intake. Participants in cluster 3, who consumed a lower proportion of carbohydrate but had higher total caloric, protein, and fat intake, had a lower risk of new-onset MASLD than those in cluster 1 after adjusting for confounders (cluster 1 as a reference; cluster 3: HR, 0.90; 95% CI, 0.82 to 0.99).
Conclusion
The study’s results highlight the critical role of macronutrient composition, particularly carbohydrate intake, in MASLD development. The findings suggest that dietary strategies focusing on optimizing macronutrients, rather than simply reducing caloric intake, may be more effective in preventing MASLD.

Review

Basic and Translational Research
Extracellular Vesicle-Mediated Network in the Pathogenesis of Obesity, Diabetes, Steatotic Liver Disease, and Cardiovascular Disease: Joonyub Lee, Won Gun Choi, Marie Rhee, Seung-Hwan Lee; Diabetes Metab J. 2025;49(3):348-367. Published online May 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0184

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Abstract PDF PubReader ePub: Extracellular vesicles (EVs) are lipid bilayer-enclosed particles carrying bioactive cargo, including nucleic acids, proteins, and lipids, facilitating intercellular and interorgan communication. In addition to traditional mediators such as hormones, metabolites, and cytokines, increasing evidence suggests that EVs are key modulators in various physiological and pathological processes, particularly influencing metabolic homeostasis and contributing to the progression of cardiometabolic diseases. This review provides an overview of the most recent insights into EV-mediated mechanisms involved in the pathogenesis of obesity, insulin resistance, diabetes mellitus, steatotic liver disease, atherosclerosis, and cardiovascular disease. EVs play a critical role in modulating insulin sensitivity, glucose homeostasis, systemic inflammation, and vascular health by transferring functional molecules to target cells. Understanding the EV-mediated network offers potential for identifying novel biomarkers and therapeutic targets, providing opportunities for EV-based interventions in cardiometabolic disease management. Although many challenges remain, this evolving field highlights the need for further research into EV biology and its translational applications in cardiovascular and metabolic health.

Original Article

Basic Research
Serotonin Regulates Lipogenesis and Endoplasmic Reticulum Stress in Alcoholic Liver Disease: Inseon Hwang, Jung Eun Nam, Wonsuk Choi, Won Gun Choi, Eunji Lee, Hyeongseok Kim, Young-Ah Moon, Jun Yong Park, Hail Kim; Received April 26, 2024 Accepted September 21, 2024 Published online February 5, 2025; DOI: https://doi.org/10.4093/dmj.2024.0215 [Epub ahead of print]

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Background
Serotonin (5-hydroxytryptamine [5-HT]) is a monoamine neurotransmitter that has various functions in central and peripheral tissues. While 5-HT is known to regulate various biological processes in liver, direct role of 5-HT and its receptors, especially 5-HT receptor 2A (HTR2A) and HTR2B, in development and progression of alcoholic liver disease (ALD) in vivo is not well understood.
Methods
Blood 5-HT level was measured from both human ALD patients and ethanol (EtOH) diet-fed mouse models. Gut-specific tryptophan hydroxylase 1 (Tph1) knockout mice, liver-specific Htr2a knockout mice, and liver-specific Htr2b knockout mice were fed with EtOH diet. Then we evaluated liver damage, hepatic steatosis, endoplasmic reticulum (ER) stress, and inflammation.
Results
Blood 5-HT concentrations are increased in both humans and mice with ALD. Both gut-specific Tph1 knockout and liver- specific Htr2a knockout mice are resistant to steatosis by down-regulating lipogenic pathways in liver of chronic EtOH diet-fed mice. Moreover, genetic inhibition of both gut-derived serotonin (GDS) synthesis and hepatic HTR2A signaling prevents ER stress in liver of chronic EtOH diet-fed mice. Additionally, we found that ablation of HTR2A signaling protects against disease progression by attenuating liver injury and inflammation in chronic plus binge EtOH diet-fed mice. Also, inhibiting HTR2A signaling ameliorates alcohol-induced liver injury and ER stress in an acute EtOH diet-fed mice model.
Conclusion
GDS directly regulates lipogenesis and ER stress via signaling through hepatic HTR2A in the context of ALD. Inhibiting HTR2A signaling protects against alcohol-induced steatosis, liver injury and disease progression in various ALD mouse models and may also provide a novel therapeutic strategy for ALD.

Citations

Citations to this article as recorded by

Oxidative stress modulation in alcohol-related liver disease: From chinese botanical drugs to exercise-based interventions
Yuting Zhu, Yuqing Jia, Enming Zhang
Frontiers in Pharmacology.2025;[Epub] CrossRef

Review

Guideline/Fact Sheet
Metabolic Dysfunction-Associated Steatotic Liver Disease in Type 2 Diabetes Mellitus: A Review and Position Statement of the Fatty Liver Research Group of the Korean Diabetes Association: Jaehyun Bae, Eugene Han, Hye Won Lee, Cheol-Young Park, Choon Hee Chung, Dae Ho Lee, Eun-Hee Cho, Eun-Jung Rhee, Ji Hee Yu, Ji Hyun Park, Ji-Cheol Bae, Jung Hwan Park, Kyung Mook Choi, Kyung-Soo Kim, Mi Hae Seo, Minyoung Lee, Nan-Hee Kim, So Hun Kim, Won-Young Lee, Woo Je Lee, Yeon-Kyung Choi, Yong-ho Lee, You-Cheol Hwang, Young Sang Lyu, Byung-Wan Lee, Bong-Soo Cha, on Behalf of the Fatty Liver Research Group of the Korean Diabetes Association; Diabetes Metab J. 2024;48(6):1015-1028. Published online November 1, 2024; DOI: https://doi.org/10.4093/dmj.2024.0541

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Since the role of the liver in metabolic dysfunction, including type 2 diabetes mellitus, was demonstrated, studies on non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) have shown associations between fatty liver disease and other metabolic diseases. Unlike the exclusionary diagnostic criteria of NAFLD, MAFLD diagnosis is based on the presence of metabolic dysregulation in fatty liver disease. Renaming NAFLD as MAFLD also introduced simpler diagnostic criteria. In 2023, a new nomenclature, steatotic liver disease (SLD), was proposed. Similar to MAFLD, SLD diagnosis is based on the presence of hepatic steatosis with at least one cardiometabolic dysfunction. SLD is categorized into metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-related/-associated liver disease, alcoholrelated liver disease, specific etiology SLD, and cryptogenic SLD. The term MASLD has been adopted by a number of leading national and international societies due to its concise diagnostic criteria, exclusion of other concomitant liver diseases, and lack of stigmatizing terms. This article reviews the diagnostic criteria, clinical relevance, and differences among NAFLD, MAFLD, and MASLD from a diabetologist’s perspective and provides a rationale for adopting SLD/MASLD in the Fatty Liver Research Group of the Korean Diabetes Association.

Citations

Citations to this article as recorded by

Bioelectrical impedance analysis parameters are superior to liver enzymes in predicting metabolic dysfunction-associated steatotic liver disease in young adults
Kyungchul Song, Yu-Jin Kwon, Eunju Lee, Hye Sun Lee, Young Hoon Youn, Su Jung Baik, Hana Lee, Joon Young Kim, Youngha Choi, Hyun Wook Chae
Internal and Emergency Medicine.2025; 20(3): 785. CrossRef
Extracellular Vesicle-Mediated Network in the Pathogenesis of Obesity, Diabetes, Steatotic Liver Disease, and Cardiovascular Disease
Joonyub Lee, Won Gun Choi, Marie Rhee, Seung-Hwan Lee
Diabetes & Metabolism Journal.2025; 49(3): 348. CrossRef
SGLT2 Inhibitors and GLP-1 Receptor Agonists in Diabetic Kidney Disease: Evolving Evidence and Clinical Application
Jae Hyun Bae
Diabetes & Metabolism Journal.2025; 49(3): 386. CrossRef

Original Articles

Metabolic Risk/Epidemiology
Comparison of SPISE and METS-IR and Other Markers to Predict Insulin Resistance and Elevated Liver Transaminases in Children and Adolescents: Kyungchul Song, Eunju Lee, Hye Sun Lee, Hana Lee, Ji-Won Lee, Hyun Wook Chae, Yu-Jin Kwon; Diabetes Metab J. 2025;49(2):264-274. Published online October 29, 2024; DOI: https://doi.org/10.4093/dmj.2024.0302

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Background
Studies on predictive markers of insulin resistance (IR) and elevated liver transaminases in children and adolescents are limited. We evaluated the predictive capabilities of the single-point insulin sensitivity estimator (SPISE) index, metabolic score for insulin resistance (METS-IR), homeostasis model assessment of insulin resistance (HOMA-IR), the triglyceride (TG)/ high-density lipoprotein cholesterol (HDL-C) ratio, and the triglyceride-glucose index (TyG) for IR and alanine aminotransferase (ALT) elevation in this population.
Methods
Data from 1,593 participants aged 10 to 18 years were analyzed using a nationwide survey. Logistic regression analysis was performed with IR and ALT elevation as dependent variables. Receiver operating characteristic (ROC) curves were generated to assess predictive capability. Proportions of IR and ALT elevation were compared after dividing participants based on parameter cutoff points.
Results
All parameters were significantly associated with IR and ALT elevation, even after adjusting for age and sex, and predicted IR and ALT elevation in ROC curves (all P<0.001). The areas under the ROC curve of SPISE and METS-IR were higher than those of TyG and TG/HDL-C for predicting IR and were higher than those of HOMA-IR, TyG, and TG/HDL-C for predicting ALT elevation. The proportions of individuals with IR and ALT elevation were higher among those with METS-IR, TyG, and TG/ HDL-C values higher than the cutoff points, whereas they were lower among those with SPISE higher than the cutoff point.
Conclusion
SPISE and METS-IR are superior to TG/HDL-C and TyG in predicting IR and ALT elevation. Thus, this study identified valuable predictive markers for young individuals.

Citations

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Is Measuring BMI and Waist Circumference as Good in Assessing Insulin Resistance as Using Bioelectrical Impedance to Measure Total Body Fat and Visceral Fat?
María Gordito Soler, Pedro Juan Tárraga López, Ángel Arturo López-González, Hernán Paublini, Emilio Martínez-Almoyna Rifá, María Teófila Vicente-Herrero, José Ignacio Ramírez-Manent
Diabetology.2025; 6(4): 32. CrossRef
Association between cardiometabolic index and postmenopausal stress urinary incontinence: a cross-sectional study from NHANES 2013 to 2018
Ting Yin, Yue He, Huifang Cong
Lipids in Health and Disease.2025;[Epub] CrossRef
Identification of pediatric MASLD using insulin resistance indices
Kyungchul Song, Eunju Lee, Hye Sun Lee, Young Hoon Youn, Su Jung Baik, Hyun Joo Shin, Hyun Wook Chae, Ji-Won Lee, Yu-Jin Kwon
JHEP Reports.2025; 7(7): 101419. CrossRef
Screening accuracy of Single-Point Insulin Sensitivity Estimator (SPISE) for metabolic syndrome: a systematic review and meta-analysis
Alireza Azarboo, Parisa Fallahtafti, Sayeh Jalali, Amirhossein Shirinezhad, Ramin Assempoor, Amirhossein Ghaseminejad-Raeini
BMC Endocrine Disorders.2025;[Epub] CrossRef

Metabolic Risk/Epidemiology
Metabolic Dysfunction-Associated Steatotic Liver Disease and All-Cause and Cause-Specific Mortality: Rosa Oh, Seohyun Kim, So Hyun Cho, Jiyoon Kim, You-Bin Lee, Sang-Man Jin, Kyu Yeon Hur, Gyuri Kim, Jae Hyeon Kim; Diabetes Metab J. 2025;49(1):80-91. Published online August 28, 2024; DOI: https://doi.org/10.4093/dmj.2024.0042

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Background
Given the association between nonalcoholic fatty liver disease and metabolic risks, a new term, metabolic dysfunction- associated steatotic liver disease (MASLD) has been proposed. We aimed to explore the association between MASLD and all-cause, cause-specific mortalities.
Methods
We included individuals with steatotic liver disease (SLD) from the Korean National Health Insurance Service. Moreover, SLD was defined as a fatty liver index ≥30. Furthermore, MASLD, metabolic alcohol-associated liver disease (MetALD), and alcoholic liver disease (ALD) with metabolic dysfunction (MD) were categorized based on alcohol consumption and MD. We also analyzed all-cause, liver-, cancer-, hepatocellular carcinoma (HCC)- and cardiovascular (CV)-related mortalities.
Results
This retrospective nationwide cohort study included 1,298,993 individuals aged 40 to 79 years for a mean follow-up duration of 9.04 years. The prevalence of MASLD, MetALD, and ALD with MD was 33.11%, 3.93%, and 1.00%, respectively. Relative to the “no SLD” group, multivariable analysis identified that MASLD (adjusted hazard ratio [aHR], 1.28; 95% confidence interval [CI], 1.26 to 1.31), MetALD (aHR, 1.38; 95% CI, 1.32 to 1.44), and ALD with MD group (aHR, 1.80; 95% CI, 1.68 to 1.93) have a significantly higher risk of all-cause mortality. Furthermore, MASLD, MetALD, ALD with MD groups showed higher liver-, cancer-, and HCC-related mortality than “no SLD” group. While all-cause specific mortalities increase from MASLD to MetALD to ALD with MD, the MetALD group shows a lower risk of CV-related mortality compared to MASLD. However, ALD with MD group still have a higher risk of CV-related mortality compared to MASLD.
Conclusion
SLD is associated with an increased risk of all-cause, liver-, cancer-, HCC-, and CV-related mortalities.

Citations

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KASL clinical practice guidelines for the management of metabolic dysfunction-associated steatotic liver disease 2025
Won Sohn, Young-Sun Lee, Soon Sun Kim, Jung Hee Kim, Young-Joo Jin, Gi-Ae Kim, Pil Soo Sung, Jeong-Ju Yoo, Young Chang, Eun Joo Lee, Hye Won Lee, Miyoung Choi, Su Jong Yu, Young Kul Jung, Byoung Kuk Jang
Clinical and Molecular Hepatology.2025; 31(Suppl): S1. CrossRef
Diagnosis and Management of Early Stages of ALD
Jordi Gratacós-Ginès, Edilmar Alvarado-Tapias, David Martí-Aguado, Hugo López-Pelayo, Ramón Bataller, Elisa Pose
Seminars in Liver Disease.2025;[Epub] CrossRef
Refining Risk Estimates of Colorectal Cancer in Steatotic Liver Disease: Insights on Methodological Challenges
Wei-Chun Cheng, Ching-Nung Wu, Pin-Nan Cheng
Clinical Gastroenterology and Hepatology.2025;[Epub] CrossRef
Synergistic benefit of thiazolidinedione and sodium-glucose cotransporter 2 inhibitor for metabolic dysfunction-associated steatotic liver disease in type 2 diabetes: a 24-week, open-label, randomized controlled trial
Minyoung Lee, Sukchul Hong, Yongin Cho, Hyungjin Rhee, Min Heui Yu, Jaehyun Bae, Yong-ho Lee, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha
BMC Medicine.2025;[Epub] CrossRef
Reply
Takefumi Kimura, Nobuharu Tamaki, Masayuki Kurosaki
Clinical Gastroenterology and Hepatology.2025;[Epub] CrossRef
High-Sensitivity C-Reactive Protein Levels in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), Metabolic Alcohol-Associated Liver Disease (MetALD), and Alcoholic Liver Disease (ALD) with Metabolic Dysfunction
Seong-Uk Baek, Jin-Ha Yoon
Biomolecules.2024; 14(11): 1468. 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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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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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

Review

Metabolic Risk/Epidemiology
Glucagon-Like Peptide-1: New Regulator in Lipid Metabolism: Tong Bu, Ziyan Sun, Yi Pan, Xia Deng, Guoyue Yuan; Diabetes Metab J. 2024;48(3):354-372. Published online April 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0277

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Glucagon-like peptide-1 (GLP-1) is a 30-amino acid peptide hormone that is mainly expressed in the intestine and hypothalamus. In recent years, basic and clinical studies have shown that GLP-1 is closely related to lipid metabolism, and it can participate in lipid metabolism by inhibiting fat synthesis, promoting fat differentiation, enhancing cholesterol metabolism, and promoting adipose browning. GLP-1 plays a key role in the occurrence and development of metabolic diseases such as obesity, nonalcoholic fatty liver disease, and atherosclerosis by regulating lipid metabolism. It is expected to become a new target for the treatment of metabolic disorders. The effects of GLP-1 and dual agonists on lipid metabolism also provide a more complete treatment plan for metabolic diseases. This article reviews the recent research progress of GLP-1 in lipid metabolism.

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Original Article

Metabolic Risk/Epidemiology
Healthy Lifestyle and the Risk of Metabolic Dysfunction-Associated Fatty Liver Disease: A Large Prospective Cohort Study: Qing Chang, Yixiao Zhang, Tingjing Zhang, Zuyun Liu, Limin Cao, Qing Zhang, Li Liu, Shaomei Sun, Xing Wang, Ming Zhou, Qiyu Jia, Kun Song, Yang Ding, Yuhong Zhao, Kaijun Niu, Yang Xia; Diabetes Metab J. 2024;48(5):971-982. Published online March 19, 2024; DOI: https://doi.org/10.4093/dmj.2023.0133

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Background
The incidence density of metabolic dysfunction-associated fatty liver disease (MAFLD) and the effect of a healthy lifestyle on the risk of MAFLD remain unknown. We evaluated the prevalence and incidence density of MAFLD and investigated the association between healthy lifestyle and the risk of MAFLD.
Methods
A cross-sectional analysis was conducted on 37,422 participants to explore the prevalence of MAFLD. A cohort analysis of 18,964 individuals was conducted to identify the incidence of MAFLD, as well as the association between healthy lifestyle and MAFLD. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) with adjustments for confounding factors.
Results
The prevalence of MAFLD, non-alcoholic fatty liver disease, and their comorbidities were 30.38%, 28.09%, and 26.13%, respectively. After approximately 70 thousand person-years of follow-up, the incidence densities of the three conditions were 61.03, 55.49, and 51.64 per 1,000 person-years, respectively. Adherence to an overall healthy lifestyle was associated with a 19% decreased risk of MAFLD (HR, 0.81; 95% CI, 0.72 to 0.92), and the effects were modified by baseline age, sex, and body mass index (BMI). Subgroup analyses revealed that younger participants, men, and those with a lower BMI experienced more significant beneficial effects from healthy lifestyle.
Conclusion
Our results highlight the beneficial effect of adherence to a healthy lifestyle on the prevention of MAFLD. Health management for improving dietary intake, physical activity, and smoking and drinking habits are critical to improving MAFLD.

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Jun‐Yan Xi, Yi‐Jing Wang, Xiao‐Heng Li, Nuo‐Min Sun, Rui‐Qi Ming, Hua‐Ling Yan, Huan‐Le Cai, Jian‐Jun Bai, Yi‐Ning Xiang, Jing Gu, Xiao Lin, Gang Liu, Yuan‐Tao Hao
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Diagnostic indicators and lifestyle interventions of metabolic-associated fatty liver disease
Tianzhu Chen, Xiang Qin, Jianping Jiang, Beihui He
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Sex differences in pathogenesis and treatment of dyslipidemia in patients with type 2 diabetes and steatotic liver disease
Tatjana Ábel, Béla Benczúr, Éva Csajbókné Csobod
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Associations of traditional healthy lifestyle and sleep quality with metabolic dysfunction-associated fatty liver disease: two population-based studies
Jialu Yang, Qi Zhang, Wanying Zhao, Bingqi Ye, Siqi Li, Zhuoyu Zhang, Jingmeng Ju, Jialin He, Min Xia, Tiantian Xiong, Yan Liu
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Sulwon Lecture 2023

Metabolic Risk/Epidemiology
Insulin Resistance, Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Clinical and Experimental Perspective: Inha Jung, Dae-Jeong Koo, Won-Young Lee; Diabetes Metab J. 2024;48(3):327-339. Published online February 2, 2024; DOI: https://doi.org/10.4093/dmj.2023.0350

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It has been generally accepted that insulin resistance (IR) and reduced insulin secretory capacity are the basic pathogenesis of type 2 diabetes mellitus (T2DM). In addition to genetic factors, the persistence of systemic inflammation caused by obesity and the associated threat of lipotoxicity increase the risk of T2DM. In particular, the main cause of IR is obesity and subjects with T2DM have a higher body mass index (BMI) than normal subjects according to recent studies. The prevalence of T2DM with IR has increased with increasing BMI during the past three decades. According to recent studies, homeostatic model assessment of IR was increased compared to that of the 1990s. Rising prevalence of obesity in Korea have contributed to the development of IR, non-alcoholic fatty liver disease and T2DM and cutting this vicious cycle is important. My colleagues and I have investigated this pathogenic mechanism on this theme through clinical and experimental studies over 20 years and herein, I would like to summarize some of our studies with deep gratitude for receiving the prestigious 2023 Sulwon Award.

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Ziping Song, Xinlei Miao, Shuang Liu, Manling Hu, Xiaoling Xie, Yuting Sun, Song Leng
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Zhixing Fan, Chaojun Yang, Xiaojing Zhao, Jing Zhang
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Original Articles

Metabolic Risk/Epidemiology
Glycemic Control Is Associated with Histological Findings of Nonalcoholic Fatty Liver Disease: Teruki Miyake, Shinya Furukawa, Bunzo Matsuura, Osamu Yoshida, Masumi Miyazaki, Akihito Shiomi, Ayumi Kanamoto, Hironobu Nakaguchi, Yoshiko Nakamura, Yusuke Imai, Mitsuhito Koizumi, Takao Watanabe, Yasunori Yamamoto, Yohei Koizumi, Yoshio Tokumoto, Masashi Hirooka, Teru Kumagi, Eiji Takesita, Yoshio Ikeda, Masanori Abe, Yoichi Hiasa; Diabetes Metab J. 2024;48(3):440-448. Published online February 2, 2024; DOI: https://doi.org/10.4093/dmj.2023.0200

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Background
Poor lifestyle habits may worsen nonalcoholic fatty liver disease (NAFLD), with progression to nonalcoholic steatohepatitis (NASH) and cirrhosis. This study investigated the association between glycemic control status and hepatic histological findings to elucidate the effect of glycemic control on NAFLD.
Methods
This observational study included 331 patients diagnosed with NAFLD by liver biopsy. Effects of the glycemic control status on histological findings of NAFLD were evaluated by comparing the following four glycemic status groups defined by the glycosylated hemoglobin (HbA1c) level at the time of NAFLD diagnosis: ≤5.4%, 5.5%–6.4%, 6.5%–7.4%, and ≥7.5%.
Results
Compared with the lowest HbA1c group (≤5.4%), the higher HbA1c groups (5.5%–6.4%, 6.5%–7.4%, and ≥7.5%) were associated with advanced liver fibrosis and high NAFLD activity score (NAS). On multivariate analysis, an HbA1c level of 6.5%– 7.4% group was significantly associated with advanced fibrosis compared with the lowest HbA1c group after adjusting for age, sex, hemoglobin, alanine aminotransferase, and creatinine levels. When further controlling for body mass index and uric acid, total cholesterol, and triglyceride levels, the higher HbA1c groups were significantly associated with advanced fibrosis compared with the lowest HbA1c group. On the other hand, compared with the lowest HbA1c group, the higher HbA1c groups were also associated with a high NAS in both multivariate analyses.
Conclusion
Glycemic control is associated with NAFLD exacerbation, with even a mild deterioration in glycemic control, especially a HbA1c level of 6.5%–7.4%, contributing to NAFLD progression.

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The association between glycemic state, R factor and Steatosis-Associated Fibrosis Estimator score in advanced liver fibrosis in patients with diabetes mellitus
Mohammadjavad Sotoudeheian, Seyed-Mohamad-Sadegh Mirahmadi, Reza Azarbad
Obesity Medicine.2025; 53: 100575. CrossRef
Combined effect of histological findings and diabetes mellitus on liver‐related events in patients with metabolic dysfunction‐associated steatotic liver disease
Akihito Shiomi, Teruki Miyake, Shinya Furukawa, Bunzo Matsuura, Osamu Yoshida, Takao Watanabe, Ayumi Kanamoto, Masumi Miyazaki, Hironobu Nakaguchi, Yoshio Tokumoto, Masashi Hirooka, Masanori Abe, Yoichi Hiasa
Hepatology Research.2024; 54(11): 1016. CrossRef
Overweight Impacts Histological Disease Activity of De Novo Metabolic Dysfunction‐Associated Steatotic Liver Disease After Liver Transplantation
Alejandro Campos‐Murguia, Lea Guetzlaff, Emily Bosselmann, Bastian Engel, Björn Hartleben, Heiner Wedemeyer, Elmar Jaeckel, Richard Taubert, Katharina Luise Hupa‐Breier
Clinical Transplantation.2024;[Epub] CrossRef

Metabolic Risk/Epidemiology
Harnessing Metabolic Indices as a Predictive Tool for Cardiovascular Disease in a Korean Population without Known Major Cardiovascular Event: Hyun-Jin Kim, Byung Sik Kim, Yonggu Lee, Sang Bong Ahn, Dong Wook Kim, Jeong-Hun Shin; Diabetes Metab J. 2024;48(3):449-462. Published online February 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0197

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Background
This study evaluated the usefulness of indices for metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and insulin resistance (IR), as predictive tools for cardiovascular disease in middle-aged Korean adults.
Methods
The prospective data obtained from the Ansan-Ansung cohort database, excluding patients with major adverse cardiac and cerebrovascular events (MACCE). The primary outcome was the incidence of MACCE during the follow-up period.
Results
A total of 9,337 patients were included in the analysis, of whom 1,130 (12.1%) experienced MACCE during a median follow-up period of 15.5 years. The metabolic syndrome severity Z-score, metabolic syndrome severity score, hepatic steatosis index, and NAFLD liver fat score were found to significantly predict MACCE at values above the cut-off point and in the second and third tertiles. Among these indices, the hazard ratios of the metabolic syndrome severity score and metabolic syndrome severity Z-score were the highest after adjusting for confounding factors. The area under the receiver operating characteristic curve (AUC) of the 10-year atherosclerotic cardiovascular disease (ASCVD) score for predicting MACCE was 0.716, and the metabolic syndrome severity Z-score had an AUC of 0.619.
Conclusion
The metabolic syndrome severity score is a highly reliable indicator and was closely associated with the 10-year ASCVD risk score in predicting MACCE in the general population. Given the specific characteristics and limitations of metabolic syndrome severity scores as well as the indices of NAFLD and IR, a more practical scoring system that considers these factors is essential to achieve greater accuracy in forecasting cardiovascular outcomes.

Citations

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Comparing non-alcoholic fatty liver disease indices in predicting the prevalence and incidence of metabolic syndrome in middle-aged adults
Byung Sik Kim, Hyun-Jin Kim, Seong Won Jeon, Kyung Hwan Kim, Dong Wook Kim, Jeong-Hun Shin
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Seung Min Chung, Kyun Hoo Kim, Jun Sung Moon, Kyu Chang Won
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Hyun-Jin Kim, Byung Sik Kim, Dong Wook Kim, Jeong-Hun Shin
The Korean Journal of Internal Medicine.2024; 39(4): 612. CrossRef

Metabolic Risk/Epidemiology
A Composite Blood Biomarker Including AKR1B10 and Cytokeratin 18 for Progressive Types of Nonalcoholic Fatty Liver Disease: Seung Joon Choi, Sungjin Yoon, Kyoung-Kon Kim, Doojin Kim, Hye Eun Lee, Kwang Gi Kim, Seung Kak Shin, Ie Byung Park, Seong Min Kim, Dae Ho Lee; Diabetes Metab J. 2024;48(4):740-751. Published online February 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0189

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Background
We aimed to evaluate whether composite blood biomarkers including aldo-keto reductase family 1 member B10 (AKR1B10) and cytokeratin 18 (CK-18; a nonalcoholic steatohepatitis [NASH] marker) have clinically applicable performance for the diagnosis of NASH, advanced liver fibrosis, and high-risk NASH (NASH+significant fibrosis).
Methods
A total of 116 subjects including healthy control subjects and patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) were analyzed to assess composite blood-based and imaging-based biomarkers either singly or in combination.
Results
A composite blood biomarker comprised of AKR1B10, CK-18, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) showed excellent performance for the diagnosis of, NASH, advanced fibrosis, and high-risk NASH, with area under the receiver operating characteristic curve values of 0.934 (95% confidence interval [CI], 0.888 to 0.981), 0.902 (95% CI, 0.832 to 0.971), and 0.918 (95% CI, 0.862 to 0.974), respectively. However, the performance of this blood composite biomarker was inferior to that various magnetic resonance (MR)-based composite biomarkers, such as proton density fat fraction/MR elastography- liver stiffness measurement (MRE-LSM)/ALT/AST for NASH, MRE-LSM+fibrosis-4 index for advanced fibrosis, and the known MR imaging-AST (MAST) score for high-risk NASH.
Conclusion
Our blood composite biomarker can be useful to distinguish progressive forms of NAFLD as an initial noninvasive test when MR-based tools are not available.

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Basic Research
DWN12088, A Prolyl-tRNA Synthetase Inhibitor, Alleviates Hepatic Injury in Nonalcoholic Steatohepatitis: Dong-Keon Lee, Su Ho Jo, Eun Soo Lee, Kyung Bong Ha, Na Won Park, Deok-Hoon Kong, Sang-In Park, Joon Seok Park, Choon Hee Chung; Diabetes Metab J. 2024;48(1):97-111. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2022.0367

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Background
Nonalcoholic steatohepatitis (NASH) is a liver disease caused by obesity that leads to hepatic lipoapoptosis, resulting in fibrosis and cirrhosis. However, the mechanism underlying NASH is largely unknown, and there is currently no effective therapeutic agent against it. DWN12088, an agent used for treating idiopathic pulmonary fibrosis, is a selective prolyl-tRNA synthetase (PRS) inhibitor that suppresses the synthesis of collagen. However, the mechanism underlying the hepatoprotective effect of DWN12088 is not clear. Therefore, we investigated the role of DWN12088 in NASH progression.
Methods
Mice were fed a chow diet or methionine-choline deficient (MCD)-diet, which was administered with DWN12088 or saline by oral gavage for 6 weeks. The effects of DWN12088 on NASH were evaluated by pathophysiological examinations, such as real-time quantitative reverse transcription polymerase chain reaction, immunoblotting, biochemical analysis, and immunohistochemistry. Molecular and cellular mechanisms of hepatic injury were assessed by in vitro cell culture.
Results
DWN12088 attenuated palmitic acid (PA)-induced lipid accumulation and lipoapoptosis by downregulating the Rho-kinase (ROCK)/AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein-1c (SREBP-1c) and protein kinase R-like endoplasmic reticulum kinase (PERK)/α subunit of eukaryotic initiation factor 2 (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) signaling cascades. PA increased but DWN12088 inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 (Ser536, Ser276) and the expression of proinflammatory genes. Moreover, the DWN12088 inhibited transforming growth factor β (TGFβ)-induced pro-fibrotic gene expression by suppressing TGFβ receptor 1 (TGFβR1)/Smad2/3 and TGFβR1/glutamyl-prolyl-tRNA synthetase (EPRS)/signal transducer and activator of transcription 6 (STAT6) axis signaling. In the case of MCD-diet-induced NASH, DWN12088 reduced hepatic steatosis, inflammation, and lipoapoptosis and prevented the progression of fibrosis.
Conclusion
Our findings provide new insights about DWN12088, namely that it plays an important role in the overall improvement of NASH. Hence, DWN12088 shows great potential to be developed as a new integrated therapeutic agent for NASH.

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