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Review
Basic and Translational Research
Article image
Heterogeneity and Clinical Relevance of Human Adipose Stromal and Progenitor Cells
Maxi Albert, Khansa Nalir, Jiawei Zhong, Lucas Massier
Diabetes Metab J. 2026;50(2):217-234.   Published online March 1, 2026
DOI: https://doi.org/10.4093/dmj.2025.1182
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Adipose stromal and progenitor cells (ASPCs) represent the largest cell population in human white adipose tissue (WAT). Despite their abundance, ASPC heterogeneity remains less well characterized compared to adipocytes or immune cells. Recent single-cell transcriptome studies provide unprecedented resolution of ASPC diversity and function. This review summarizes state-of-the-art approaches, including high-resolution single-cell methods, classical lineage and functional assays, to define ASPC populations. By systematically comparing recent datasets, we identify evidence for at least eight distinct ASPC-subtypes, which demonstrate specific marker genes and putative functional diversity. Along the adipogenic trajectory, these include uncommitted multipotent progenitors, intermediate and committed preadipocytes, and premature adipocytes. Additional populations comprise specialized anti-adipogenic, profibrotic, inflammatory, and fibroblast-like ASPCs. Other cell types are not consistently detected across studies, reflecting both biological and methodological variability, and the need for further validation studies. Better understanding of ASPC heterogeneity may improve the clinical assessment of metabolic disorders and support their treatment. We further discuss subtype-specific (dys)functions linked to fibrosis, inflammation and impaired adipogenesis and describe their increased abundance in metabolic disease. Together, this review integrates current knowledge on ASPC heterogeneity and highlights its clinical relevance, aiming to provide a unified framework for future studies on WAT remodeling and metabolic dysfunction.
Original Articles
Pharmacotherapy
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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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  • 1 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   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.

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  • Metformin beyond Glycemic Control: New Mechanistic Insights and Expanding Therapeutic Horizons
    Eugene Han, Jung Ho Nam, Insuk Lee, Cheol Ryong Ku, Yong-ho Lee
    Diabetes & Metabolism Journal.2026; 50(3): 435.     CrossRef
Basic and Translational Research
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Hepatocyte RAP1A Deletion Impairs Lipid Catabolism and Worsens Steatosis via Autophagy Activation
Xiujuan Wei, Yinxu Fu, Yu Fang, Xi Lin, Zhonggui Luo, Keyi Li, Kaiqiang Yang, Ting Fu, Liqin Jin, Jianxin Lyu, Qiongya Zhao
Received May 1, 2025  Accepted August 25, 2025  Published online November 24, 2025  
DOI: https://doi.org/10.4093/dmj.2025.0388    [Epub ahead of print]
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Metabolic disorders such as obesity, type 2 diabetes mellitus, and fatty liver disease are often linked to excessive hepatic lipid accumulation. This study aimed to determine the role of Ras-related protein 1a (RAP1A) in regulating hepatic lipid metabolism and to elucidate how RAP1A impacts metabolic dysfunction-associated fatty liver disease progression. We focused on RAP1A’s influence on liver lipid homeostasis and its connection to metabolic health.
Methods
A liver-specific Rap1a knockout (LKO) mouse model was generated and fed a high-fat diet to induce obesity and steatosis. Metabolic phenotyping (body weight, adiposity, glucose tolerance, insulin sensitivity) and liver analyses (histology, triglyceride/ cholesterol content, and gene expression profiling) were performed. In parallel, cultured hepatocyte models (alpha mouse liver 12 [AML12] cells) with RAP1A knockdown or overexpression were used to assess cellular lipid accumulation, fatty acid oxidation, and mechanistic pathways. Mitochondrial function assays, autophagy analysis, and extracellular signal-regulated kinase (ERK) signaling evaluations were conducted, including interventions with an ERK activator and autophagy inhibitor to probe pathway involvement.
Results
LKO mice developed increased adiposity and hepatic steatosis with significantly elevated liver triglycerides, cholesterol, and lipid droplet accumulation, despite unchanged caloric intake. They also exhibited impaired glucose tolerance and insulin resistance, indicating pronounced metabolic dysfunction. RAP1A deficiency led to dysregulated hepatic lipid gene expression—mainly downregulating genes for fatty acid oxidation and lipid catabolism—consistent with exacerbated lipid accumulation. Hepatocytes lacking RAP1A showed similar lipid accumulation, reduced fatty acid oxidation capacity, and altered expression of lipid metabolic enzymes. Mechanistically, RAP1A-deficient livers and cells displayed activated autophagy, particularly mitophagy. RAP1A was found to localize to mitochondrial membranes, and its loss was associated with reduced ERK phosphorylation. Notably, pharmacological activation of the ERK pathway restored ERK phosphorylation and significantly alleviated triglyceride accumulation in RAP1A-knockdown hepatocytes, rescuing the expression of key lipid breakdown enzymes. Conversely, inhibition of excessive autophagy in RAP1A-deficient cells also partially normalized lipid levels. These findings demonstrate that loss of RAP1A triggers hepatic lipid accumulation and metabolic dysregulation through coordinated effects on lipid metabolism genes, mitophagy, and ERK signaling.
Conclusion
RAP1A is a critical regulator of hepatic lipid metabolism, safeguarding against diet-induced steatosis and metabolic dysfunction. Its absence leads to lipid buildup and impaired metabolic homeostasis via disruptions in lipid accumulation, mitochondrial function, autophagy, and ERK signaling.
Metabolic Risk/Epidemiology
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Ultra-Processed Food Intake and Risk of Type 2 Diabetes Mellitus: A Dose-Response Meta-Analysis of Prospective Studies
Yujin Kim, Yoonkyoung Cho, Jin Eui Kim, Dong Hoon Lee, Hannah Oh
Diabetes Metab J. 2025;49(5):1064-1074.   Published online June 9, 2025
DOI: https://doi.org/10.4093/dmj.2024.0706
Correction in: Diabetes Metab J 2026;50(1):211
  • 14,266 View
  • 495 Download
  • 10 Web of Science
  • 8 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Although some studies suggest a positive association between ultra-processed food (UPF) intake and type 2 diabetes mellitus (T2DM), little is known about the exact shape and risks associated with different units (percentage of g/day, absolute g/day, serving/day) of UPF intake and whether the association is independent of diet quality, total energy intake, and body mass index (BMI).
Methods
Prospective studies published through January 2024 were identified by searching PubMed, Embase, and Web of Science. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated using random-effects models. A nonlinear dose-response meta-analysis was conducted using restricted cubic spline analysis.
Results
After screening 569 publications, a total of 12 prospective cohort studies were included. Comparing the highest vs. lowest categories of intake, summary RR for T2DM risk was 1.48 (95% CI, 1.36 to 1.61). Higher summary RRs were observed among studies from Europe and North America. Among individual UPF subgroups, processed meats (summary RR, 1.34; 95% CI, 1.16 to 1.54) were positively associated, whereas ultra-processed cereals and breads (0.98; 95% CI, 0.97 to 0.99) and packaged savory snacks (0.92; 95% CI, 0.88 to 0.95) were inversely associated. The summary RRs associated with every 10% (of g/day), 100-g/day, and 1-serving/day increase in UPF intake were 1.14 (95% CI, 1.11 to 1.17), 1.05 (95% CI, 1.03 to 1.06), and 1.04 (95% CI, 1.03 to 1.05), respectively. The dose-response curve for absolute g/d intake suggested nonlinearity, showing a steeper risk increase approximately at >300 g/day. The associations persisted after adjustment for diet quality, energy intake, or BMI.
Conclusion
Our data suggest that UPF intake increases diabetes risk, with a potential threshold effect at 300 g/day.

Citations

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  • Ultra-Processed Food Intake and Risk of Type 2 Diabetes Mellitus: A Dose-Response Meta-Analysis of Prospective Studies (Diabetes Metab J 2025;49:1064-74)
    Lirong Hu, Aiji Chen, Gang Tian
    Diabetes & Metabolism Journal.2026; 50(1): 194.     CrossRef
  • Ultra-Processed Food Intake and Risk of Type 2 Diabetes Mellitus: A Dose-Response Meta-Analysis of Prospective Studies (Diabetes Metab J 2025;49:1064-74)
    Yujin Kim, Hannah Oh
    Diabetes & Metabolism Journal.2026; 50(1): 208.     CrossRef
  • Dietary Patterns, Cooking Methods, and Their Association with Prediabetes Risk Markers in Romanian University Students: A Cross-Sectional Analysis
    Teodora Piroș, Raluca Lupusoru, Lavinia Cristina Moleriu, Călin Muntean, Radu Dumitru Moleriu, Dora Mihalea Cîmpian, Mădălina Gabriela Cincu, Elena Gabriela Strete, Amalia Gabriela Timofte, Ruxandra-Cristina Marin
    Nutrients.2026; 18(6): 977.     CrossRef
  • Commentary on the Dietary Guidelines for Americans 2026–2030
    Douglas Taren, Robert Bandsma, Alejandra Cantoral, Chi Chen, Brian Finck, Corrine Hanson, Gang Hu, Nicole Kellow, Kathleen Holton, Hanqi Luo, Joshua Miller, Maurizio Muscaritoli, Muzi Na, Rachel Novotny, Omar Ramos-Lopez, Manuel Ruz, Krista Varady, Saroja
    Nutrition Reviews.2026;[Epub]     CrossRef
  • Associations between dietary food categories, epigenetic age acceleration and low-grade inflammation in the Lifelines-DEEP cohort
    Laura Bordoni, Fatemeh Mansouri, Chiara Rucci, João Agostinho de Sousa, Ferdinand von Meyenn
    Clinical Nutrition.2026; 63: 106703.     CrossRef
  • Ultra-processed food consumption and the trajectory of cardio-renal-metabolic multimorbidity: insights from multi-state modelling
    Shuzhen Zhao, Chengnan Guo, Xin Zhang, Yi Li, Jingkun Hu, Jiayi Huang, Luojia Dai, Zhenqiu Liu, Tiejun Zhang
    Food & Function.2026; 17(14): 6478.     CrossRef
  • The association between ultra-processed food consumption and incidence of cardio-renal-metabolic multimorbidity: Tehran Lipid and Glucose Study
    Emad Alem, Somayeh Hosseinpour-Niazi, Parvin Mirmiran, Fereidoun Azizi
    Nutrition, Metabolism and Cardiovascular Diseases.2026; : 104855.     CrossRef
  • Trends in sales of sugar-sweetened beverages and associated type 2 diabetes burden in nine African countries: an ecological time-series analysis
    Caroline H. Karugu, Gershim Asiki, Senzo Mthembu, Samuel Iddi, Peter M. Kaberia, Shukri F. Mohamed, Richard E. Sanya, Sylvia Kiwuwa-Muyingo, Stefanie Vandevijvere, Charles Agyemang
    Global Health Action.2025;[Epub]     CrossRef
Review
Basic and Translational Research
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Metabolic Sparks in the Liver: Metabolic and Epigenetic Reprogramming in Hepatic Stellate Cells Activation and Its Implications for Human Metabolic Diseases
Yeon Jin Roh, Hyeonki Kim, Dong Wook Choi
Diabetes Metab J. 2025;49(3):368-385.   Published online May 1, 2025
DOI: https://doi.org/10.4093/dmj.2025.0195
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  • 10 Web of Science
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AbstractAbstract PDFPubReader   ePub   
The liver plays a fundamental role in metabolic homeostasis, integrating systemic fuel utilization with the progression of various metabolic diseases. Hepatic stellate cells (HSCs) are a key nonparenchymal cell type in the liver, which is essential for maintaining hepatic architecture in their quiescent state. However, upon chronic liver injury or metabolic stress, HSCs become activated, leading to excessive extracellular matrix deposition and pro-fibrotic signaling, ultimately positioning them as key players in liver pathology. Emerging evidence highlights the critical roles of metabolic reprogramming and epigenetic regulation in HSCs activation. HSCs activation is driven by both intrinsic fuel metabolism reprogramming and extrinsic metabolic cues from the microenvironment, while the metabolic intermediates actively reshape the epigenetic landscape, reinforcing fibrogenic transcriptional programs. In this review, we summarize recent advances in understanding how metabolic and epigenetic alterations drive HSCs activation, thereby shaping transcriptional programs that sustain fibrosis, and discuss potential therapeutic strategies to target these interconnected pathways in human metabolic diseases.

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  • Breaking Glycolysis Barriers to Immunotherapy with Nanomedicines
    Miya Zhang, Yanhong Ren, Jiaping Li, Jiaji Yu, Qianqi Li, Heng Zhao, Zheng Wang, Xiaoyuan Chen, Junjie Cheng
    ACS Nano Medicine.2026; 1(1): 149.     CrossRef
  • Burden of MASLD and liver fibrosis: evidence from Phenome India cohort
    Meghana Arvind, Anshul Verma, Sreeshma Raj K, Satyartha Prakash, Vignesh S. Kumar, Mohammad Azhar Uddin, Ayushi Narayan, Mamta Rathore, Nancy Rawat, Ankita Sahu, Yogesh Kumar, Pulkit Hasmukhbhai Leuva, Monika Sharma, Rajesh S, Dwaipayan Saha, Ankita Mridh
    The Lancet Regional Health - Southeast Asia.2026; 45: 100723.     CrossRef
  • Beyond Organ-Specific Therapies: A Unified Approach to Multi-Organ Fibrosis
    Ziyan Pan, Shadi Zerehpoosh, Shu-Chi Wang, Necati Örmeci, Won Kim, Mohammed Eslam
    Drug Design, Development and Therapy.2026; Volume 20: 1.     CrossRef
  • α-Hederin Alleviates Endoplasmic Reticulum Stress by Upregulating TRIM38 Expression, Thereby Inhibiting Hepatic Stellate Cell Activation and Liver Fibrosis
    Wei Xu, Yang Yang, Fuqiang Li, Can Li, Gaojun Tang, Baofang Zhang, Mingliang Cheng
    Biomedicines.2026; 14(4): 829.     CrossRef
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    Xiang Li, Xuemeng Yang, Yanyu Xu, Qianqian Zhao, Yang Xu, Jiahao Geng, Donghao Yin, Jiabo Wang, Xinhua Song
    Journal of Ethnopharmacology.2026; 365: 121571.     CrossRef
  • Loss of immunometabolic adaptability in MASH: gut-derived signals drive macrophage reprogramming and fibrosis
    Yan Li, Yuyuan Hu, Yuan He, Yuhang Yang, Dingwen Xue, Erkui Xue, Jinghan Jia, Wei Zhang, Jinxi Wang
    Frontiers in Immunology.2026;[Epub]     CrossRef
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    Sara Mohammadi Miyanroodan, Muhammad Sohail
    Journal of Drug Delivery Science and Technology.2026; 122: 108447.     CrossRef
  • Pirfenidone Sensitizes Hepatic Stellate Cells to Ferroptosis by Reprogramming Glutamine and Serine Metabolism for GSH Depletion
    Jia Li, Li Wang, Yakun Li, Junyu Wang, Manon Buist-Homan, Klaas Nico Faber, Han Moshage
    Antioxidants.2026; 15(5): 552.     CrossRef
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    Akram S. Al-Mughalles, Junhu Ma, Hong Ma, Cuiyu Zhang, Huangjin Xiao, Xiaoyuan Ma, Qian Zhang, Chenggang Jia, Hua Han, Bi-sen Ding, Shuya Zhang
    Cell Communication and Signaling.2026;[Epub]     CrossRef
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    Amedeo Lonardo, Ralf Weiskirchen
    Metabolites.2026; 16(8): 529.     CrossRef
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    Cong Zhang, Yingying Song, Yurou Huang, Yingxi Luo, Han Zhao, Yani Huang, Haixia Zhao, Zhenpeng Qiu
    Phytomedicine.2026; : 158673.     CrossRef
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    Fangqing Zhao, Xuan Niu, Ge Song, Lijie Wang, Yisheng Fu, Shuwen Li, Xinxin Gu, Qingkun Wang, Jiao Luo
    Journal of Translational Medicine.2025;[Epub]     CrossRef
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    Amedeo Lonardo, Ralf Weiskirchen
    Exploration of Digestive Diseases.2025;[Epub]     CrossRef
Original Articles
Basic and Translational Research
Article image
Macrophage-Specific Progranulin Deficiency Prevents Diet-Induced Obesity through the Inhibition of Hypothalamic and Adipose Tissue Inflammation
Chan Hee Lee, Chae Beom Park, Hyun-Kyong Kim, Won Hee Jang, Se Hee Min, Jae Bum Kim, Min-Seon Kim
Diabetes Metab J. 2025;49(4):784-797.   Published online March 11, 2025
DOI: https://doi.org/10.4093/dmj.2024.0486
  • 7,109 View
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  • 6 Web of Science
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Chronic low-grade inflammation in multiple metabolic organs contributes to the development of insulin resistance induced by obesity. Progranulin (PGRN) is an evolutionarily-conserved secretory protein implicated in immune modulation. The generalized deletion of the PGRN-encoded Grn gene improves insulin resistance and glucose intolerance in obese mice fed a high-fat diet (HFD). However, it remains unclear which cells or organs are responsible for the beneficial metabolic effect of Grn depletion.
Methods
Considering the critical role of macrophages in HFD-induced obesity and inflammation, we generated mice with a macrophage-specific Grn depletion (Grn-MΦKO mice) by mating lysozyme M (LysM)-Cre and Grn-floxed mice. Body weight, food intake, energy expenditure, and glucose and insulin tolerance were compared between Grn-MΦKO mice and their wildtype (WT) controls under normal chow diet (NCD)- or HFD-fed conditions. We also examined macrophage activation and inflammation- related gene expression in the visceral adipose tissue and hypothalamus along with insulin and leptin signaling.
Results
Grn-MΦKO mice showed no alteration in metabolic phenotypes under NCD-fed conditions. However, upon HFD feeding, these mice exhibited less weight gain and improved glucose and insulin tolerance compared to WT mice. Moreover, HFD-induced macrophage activation and proinflammatory cytokine expression were significantly reduced in both the adipose tissue and hypothalamus of Grn-MΦKO mice, while HFD-induced impairments in leptin and insulin signaling showed improvement.
Conclusion
Macrophage-derived PGRN and possibly other Grn products play a critical role in the development of HFD-induced obesity, tissue inflammation, and impaired hormonal signaling in both central and peripheral metabolic organs.

Citations

Citations to this article as recorded by  
  • Tissue-specific immune and MAPK signatures in models of reduced Progranulin and Western diet
    Andrea R. Merchak, Maria Elizabeth de Sousa Rodrigues, Cassandra Cole, Noelle Neighbarger, Nilay Bhavsar, Rebecca L. Wallings, Valerie Joers, Jianjun Chang, Sean D. Kelly, Timothy R. Sampson, Malú Gámez Tansey
    Neurobiology of Disease.2026; 220: 107287.     CrossRef
  • The immunometabolic network in obesity-associated insulin resistance: a systemic multi-organ and multi-cellular perspective
    Yi Zhang, Haixin Ding, Xue Zhao, Yutong Li, Pengling Ge
    International Immunopharmacology.2026; 177: 116528.     CrossRef
  • Role of Macrophage-Derived Progranulin in Energy and Glucose Metabolism
    Do Kyeong Song
    Diabetes & Metabolism Journal.2025; 49(4): 580.     CrossRef
  • The Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction
    Milton Packer
    JACC.2025; 86(16): 1269.     CrossRef
  • Serum Granulin Concentrations Are Elevated in Prediabetes and Newly Diagnosed Diabetes: A Cross-Sectional Study
    Yu-Hsuan Chou, Yuan Kao, Ka Chon Chan, Hsuan-Wen Chou, Yu-Cheng Liang, Hung-Tsung Wu, Horng-Yih Ou
    Journal of Clinical Medicine.2025; 14(18): 6566.     CrossRef
  • TNFR2 signaling in musculoskeletal diseases: Implications for rheumatoid arthritis and osteoarthritis
    Emily Qian, Ryan S MacLeod, Chuan-Ju Liu
    Journal of Leukocyte Biology.2025;[Epub]     CrossRef
Metabolic Risk/Epidemiology
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Trends in Metabolically Unhealthy Obesity by Age, Sex, Race/Ethnicity, and Income among United States Adults, 1999 to 2018
Wen Zeng, Weijiao Zhou, Junlan Pu, Juan Li, Xiao Hu, Yuanrong Yao, Shaomei Shang
Diabetes Metab J. 2025;49(3):475-484.   Published online February 25, 2025
DOI: https://doi.org/10.4093/dmj.2024.0364
  • 7,665 View
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
This study aimed to estimate temporal trends in metabolically unhealthy obesity (MUO) among United States (US) adults by age, sex, race/ethnicity, and income from 1999 to 2018.
Methods
We included 17,230 non-pregnant adults from a nationally representative cross-sectional study, the National Health and Nutrition Examination Survey (NHANES). MUO was defined as body mass index ≥30 kg/m2 with any metabolic disorders in blood pressure, blood glucose, and blood lipids. The age-adjusted percentage of MUO was calculated, and linear regression models estimated trends in MUO.
Results
The weighted mean age of adults was 47.28 years; 51.02% were male, 74.64% were non-Hispanic White. The age-adjusted percentage of MUO continuously increased in adults across all subgroups during 1999–2018, although with different magnitudes (all P<0.05 for linear trend). Adults aged 45 to 64 years consistently had higher percentages of MUO from 1999–2000 (34.25%; 95% confidence interval [CI], 25.85% to 42.66%) to 2017–2018 (42.03%; 95% CI, 35.09% to 48.97%) than the other two age subgroups (P<0.05 for group differences). The age-adjusted percentage of MUO was the highest among non-Hispanic Blacks while the lowest among non-Hispanic Whites in most cycles. Adults with high-income levels generally had lower MUO percentages from 1999–2000 (22.63%; 95% CI, 17.00% to 28.26%) to 2017–2018 (32.36%; 95% CI, 23.87% to 40.85%) compared with the other two subgroups.
Conclusion
This study detected a continuous linear increasing trend in MUO among US adults from 1999 to 2018. The persistence of disparities by age, race/ethnicity, and income is a cause for concern. This calls for implementing evidence-based, structural, and effective MUO prevention programs.

Citations

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  • Repercussions of racial, gender, and class inequities on food and nutrition conditions: Implications for public health
    Tatiana Palotta Minari
    Nutrition.2026; 142: 112995.     CrossRef
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    Nur Indrawaty Lipoeto, Nola Vita Sari, Dewi Susanti Febri, Mirnawati Mirnawati
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    BMC Public Health.2026;[Epub]     CrossRef
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    Young Sang Lyu, Sang Yong Kim
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    Amedeo Lonardo, Ralf Weiskirchen
    Exploration of Medicine.2025;[Epub]     CrossRef
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    JIANRONG ZHANG
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    European Journal of Medical Research.2025;[Epub]     CrossRef
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    Hajung Joo, Eunchae Lee, Juyeong Kim, Seohyun Hong, Jinyoung Jeong, Jaehyun Kong, Yoon Lee, Hyunjee Kim, Lee Smith, Ho Geol Woo, Dong Keon Yon
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Lifestyle and Behavioral Interventions
Article image
Impact of Meal Frequency on Insulin Resistance in Middle-Aged and Older Adults: A Prospective Cohort Study
Ha-Eun Ryu, Jong Hee Lee, Byoungjin Park, Seok-Jae Heo, Yu-Jin Kwon
Diabetes Metab J. 2025;49(2):311-320.   Published online November 13, 2024
DOI: https://doi.org/10.4093/dmj.2024.0407
  • 33,329 View
  • 308 Download
  • 3 Web of Science
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Insulin resistance (IR) is central to metabolic disorders and significantly influenced by diet. Studies on meal frequency (MF) and metabolic indicators have shown mixed results. This study explores the link between MF and IR in middle-aged and older adults.
Methods
This prospective cohort study included 4,570 adults aged 40 to 69 years from the Korean Genome and Epidemiologic Study. MF were divided into two groups based on whether they consumed three or more, or fewer than three, meals daily. IR was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR); participants were classified as IR if their HOMA-IR value was ≥2.5. Multiple Cox proportional hazard regression analyses were conducted to examine the association between MF and the incidence of IR.
Results
After adjusting for all variables, individuals in the MF ≥3 group showed a reduced incidence of IR compared to those in the MF <3 group (hazard ratio, 0.880; 95% confidence interval, 0.782 to 0.990). Additionally, subgroup analyses by sex, diabetes mellitus (DM), and body mass index (BMI) showed that this association persisted only in men, individuals without DM, and those with a BMI <25.
Conclusion
Our findings indicate that a higher MF among middle-aged and older adults is associated with a reduced incidence of IR. However, this association was maintained only in men, individuals without DM, and those without obesity.

Citations

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  • Prevalence and lifestyle factors associated with sarcopenic obesity among older adults with central obesity: A cross-sectional study using CHARLS
    Jiaojiao Lin, Zhaozhao Zhu, Yi Zhang
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    Ja Young Jeon
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    Ha-Eun Ryu, Jong Hee Lee, Byoungjin Park, Seok-Jae Heo, Yu-Jin Kwon
    Diabetes & Metabolism Journal.2025; 49(4): 912.     CrossRef
Reviews
Others
Article image
T-Cell Senescence in Human Metabolic Diseases
Ha Thi Nga, Thi Linh Nguyen, Hyon-Seung Yi
Diabetes Metab J. 2024;48(5):864-881.   Published online August 28, 2024
DOI: https://doi.org/10.4093/dmj.2024.0140
  • 24,069 View
  • 496 Download
  • 35 Web of Science
  • 41 Crossref
AbstractAbstract PDFPubReader   ePub   
Immunosenescence denotes a state of dysregulated immune cell function characterized by a confluence of factors, including arrested cell cycle, telomere shortening, markers of cellular stress, mitochondrial dysfunction, loss of proteostasis, epigenetic reprogramming, and secretion of proinflammatory mediators. This state primarily manifests during the aging process but can also be induced in various pathological conditions, encompassing chronic viral infections, autoimmune diseases, and metabolic disorders. Age-associated immune system alterations extend to innate and adaptive immune cells, with T-cells exhibiting heightened susceptibility to immunosenescence. In particular, senescent T-cells have been identified in the context of metabolic disorders such as obesity, diabetes, and cardiovascular diseases. Recent investigations suggest a direct link between T-cell senescence, inflammation, and insulin resistance. The perturbation of biological homeostasis by senescent T-cells appears intricately linked to the initiation and progression of metabolic diseases, particularly through inflammation-mediated insulin resistance. Consequently, senescent T-cells are emerging as a noteworthy therapeutic target. This review aims to elucidate the intricate relationship between metabolic diseases and T-cell senescence, providing insights into the potential roles of senescent T-cells in the pathogenesis of metabolic disorders. Through a comprehensive examination of current research findings, this review seeks to contribute to a deeper understanding of the complex interplay between immunosenescence and metabolic health.

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Pathophysiology
Article image
Protein Arginine Methyltransferases: Emerging Targets in Cardiovascular and Metabolic Disease
Yan Zhang, Shibo Wei, Eun-Ju Jin, Yunju Jo, Chang-Myung Oh, Gyu-Un Bae, Jong-Sun Kang, Dongryeol Ryu
Diabetes Metab J. 2024;48(4):487-502.   Published online July 24, 2024
DOI: https://doi.org/10.4093/dmj.2023.0362
  • 10,132 View
  • 301 Download
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AbstractAbstract PDFPubReader   ePub   
Cardiovascular diseases (CVDs) and metabolic disorders stand as formidable challenges that significantly impact the clinical outcomes and living quality for afflicted individuals. An intricate comprehension of the underlying mechanisms is paramount for the development of efficacious therapeutic strategies. Protein arginine methyltransferases (PRMTs), a class of enzymes responsible for the precise regulation of protein methylation, have ascended to pivotal roles and emerged as crucial regulators within the intrinsic pathophysiology of these diseases. Herein, we review recent advancements in research elucidating on the multifaceted involvements of PRMTs in cardiovascular system and metabolic diseases, contributing significantly to deepen our understanding of the pathogenesis and progression of these maladies. In addition, this review provides a comprehensive analysis to unveil the distinctive roles of PRMTs across diverse cell types implicated in cardiovascular and metabolic disorders, which holds great potential to reveal novel therapeutic interventions targeting PRMTs, thus presenting promising perspectives to effectively address the substantial global burden imposed by CVDs and metabolic disorders.

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Basic Research
Article image
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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AbstractAbstract PDFPubReader   ePub   
Mitochondrial stress and the dysregulated mitochondrial unfolded protein response (UPRmt) are linked to various diseases, including metabolic disorders, neurodegenerative diseases, and cancer. Mitokines, signaling molecules released by mitochondrial stress response and UPRmt, are crucial mediators of inter-organ communication and influence systemic metabolic and physiological processes. In this review, we provide a comprehensive overview of mitokines, including their regulation by exercise and lifestyle interventions and their implications for various diseases. The endocrine actions of mitokines related to mitochondrial stress and adaptations are highlighted, specifically the broad functions of fibroblast growth factor 21 and growth differentiation factor 15, as well as their specific actions in regulating inter-tissue communication and metabolic homeostasis. Finally, we discuss the potential of physiological and genetic interventions to reduce the hazards associated with dysregulated mitokine signaling and preserve an equilibrium in mitochondrial stress-induced responses. This review provides valuable insights into the mechanisms underlying mitochondrial regulation of health and disease by exploring mitokine interactions and their regulation, which will facilitate the development of targeted therapies and personalized interventions to improve health outcomes and quality of life.

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Basic Research
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The Link between Mitochondrial Dysfunction and Sarcopenia: An Update Focusing on the Role of Pyruvate Dehydrogenase Kinase 4
Min-Ji Kim, Ibotombi Singh Sinam, Zerwa Siddique, Jae-Han Jeon, In-Kyu Lee
Diabetes Metab J. 2023;47(2):153-163.   Published online January 12, 2023
DOI: https://doi.org/10.4093/dmj.2022.0305
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AbstractAbstract PDFPubReader   ePub   
Sarcopenia, defined as a progressive loss of muscle mass and function, is typified by mitochondrial dysfunction and loss of mitochondrial resilience. Sarcopenia is associated not only with aging, but also with various metabolic diseases characterized by mitochondrial dyshomeostasis. Pyruvate dehydrogenase kinases (PDKs) are mitochondrial enzymes that inhibit the pyruvate dehydrogenase complex, which controls pyruvate entry into the tricarboxylic acid cycle and the subsequent adenosine triphosphate production required for normal cellular activities. PDK4 is upregulated in mitochondrial dysfunction-related metabolic diseases, especially pathologic muscle conditions associated with enhanced muscle proteolysis and aberrant myogenesis. Increases in PDK4 are associated with perturbation of mitochondria-associated membranes and mitochondrial quality control, which are emerging as a central mechanism in the pathogenesis of metabolic disease-associated muscle atrophy. Here, we review how mitochondrial dysfunction affects sarcopenia, focusing on the role of PDK4 in mitochondrial homeostasis. We discuss the molecular mechanisms underlying the effects of PDK4 on mitochondrial dysfunction in sarcopenia and show that targeting mitochondria could be a therapeutic target for treating sarcopenia.

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Basic Research
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Revisiting the Bacterial Phylum Composition in Metabolic Diseases Focused on Host Energy Metabolism
Yeonmi Lee, Hui-Young Lee
Diabetes Metab J. 2020;44(5):658-667.   Published online July 9, 2020
DOI: https://doi.org/10.4093/dmj.2019.0220
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AbstractAbstract PDFPubReader   ePub   

Over a hundred billion bacteria are found in human intestines. This has emerged as an environmental factor in metabolic diseases, such as obesity and related diseases. The majority of these bacteria belong to two dominant phyla, Bacteroidetes and Firmicutes. Since the ratio of Firmicutes to Bacteroidetes increases in people with obesity and in various animal models, it has been assumed that phylum composition causes the increase in occurrence of metabolic diseases over the past decade. However, this assumption has been challenged by recent studies that have found even an opposite association of phylum composition within metabolic diseases. Moreover, the gut microbiota affects host energy metabolism in various ways including production of metabolites and interaction with host intestinal cells to regulate signaling pathways that affect energy metabolism. However, the direct effect of gut bacteria on host energy intake, such as energy consumption by the bacteria itself and its effects on intestinal energy absorption, has been underestimated. This review aims to discuss whether increased ratio of Firmicutes to Bacteroidetes is associated with the development of metabolic diseases, and whether energy competition between the bacteria and host is a missing part of the mechanism linking gut microbiota to metabolic diseases.

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Original Article
Metabolic Risk/Epidemiology
Article image
Sex-, Age-, and Metabolic Disorder-Dependent Distributions of Selected Inflammatory Biomarkers among Community-Dwelling Adults
So Mi Jemma Cho, Hokyou Lee, Jee-Seon Shim, Hyeon Chang Kim
Diabetes Metab J. 2020;44(5):711-725.   Published online April 16, 2020
DOI: https://doi.org/10.4093/dmj.2019.0119
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background

Inflammatory cytokines are increasingly utilized to detect high-risk individuals for cardiometabolic diseases. However, with large population and assay methodological heterogeneity, no clear reference currently exists.

 Methods

Among participants of the Cardiovascular and Metabolic Diseases Etiology Research Center cohort, of community-dwelling adults aged 30 to 64 without overt cardiovascular diseases, we presented distributions of tumor necrosis factor (TNF)-α and -β, interleukin (IL)-1α, -1β, and 6, monocyte chemoattractant protein (MCP)-1 and -3 and high sensitivity C-reactive protein (hsCRP) with and without non-detectable (ND) measurements using multiplex enzyme-linked immunosorbent assay. Then, we compared each markers by sex, age, and prevalence of type 2 diabetes mellitus, hypertension, and dyslipidemia, using the Wilcoxon Rank-Sum Test.

 Results

In general, there were inconsistencies in direction and magnitude of differences in distributions by sex, age, and prevalence of cardiometabolic disorders. Overall, the median and the 99th percentiles were higher in men than in women. Older participants had higher TNF-α, high sensitivity IL-6 (hsIL-6), MCP-1, hsCRP, TNF-β, and MCP-3 median, after excluding the NDs. Participants with type 2 diabetes mellitus had higher median for all assayed biomarkers, except for TNF-β, IL-1α, and MCP-3, in which the medians for both groups were 0.00 due to predominant NDs. Compared to normotensive group, participants with hypertension had higher TNF-α, hsIL-6, MCP-1, and hsCRP median. When stratifying by dyslipidemia prevalence, the comparison varied significantly depending on the treatment of NDs.

 Conclusion

Our findings provide sex-, age-, and disease-specific reference values to improve risk prediction and diagnostic performance for inflammatory diseases in both population- and clinic-based settings.

Citations

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Reviews
Pathophysiology
Regulation of Systemic Glucose Homeostasis by T Helper Type 2 Cytokines
Yea Eun Kang, Hyun Jin Kim, Minho Shong
Diabetes Metab J. 2019;43(5):549-559.   Published online October 24, 2019
DOI: https://doi.org/10.4093/dmj.2019.0157
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AbstractAbstract PDFPubReader   ePub   

Obesity results in an inflammatory microenvironment in adipose tissue, leading to the deterioration of tissue protective mechanisms. Although recent studies suggested the importance of type 2 immunity in an anti-inflammatory microenvironment in adipose tissue, the regulatory effects of T helper 2 (Th2) cytokines on systemic metabolic regulation are not fully understood. Recently, we identified the roles of the Th2 cytokine (interleukin 4 [IL-4] and IL-13)-induced adipokine, growth differentiation factor 15 (GDF15), in adipose tissue in regulating systemic glucose metabolism via signal transducer and activator of transcription 6 (STAT6) activation. Moreover, we showed that mitochondrial oxidative phosphorylation is required to maintain these macrophage-regulating autocrine and paracrine signaling pathways via Th2 cytokine-induced secretion of GDF15. In this review, we discuss how the type 2 immune response and Th2 cytokines regulate metabolism in adipose tissue. Specifically, we review the systemic regulatory roles of Th2 cytokines in metabolic disease and the role of mitochondria in maintenance of type 2 responses in adipose tissue homeostasis.

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Clinical Diabetes & Therapeutics
Nonalcoholic Fatty Liver Disease and Diabetes: Part II: Treatment
Kyung-Soo Kim, Byung-Wan Lee, Yong Jin Kim, Dae Ho Lee, Bong-Soo Cha, Cheol-Young Park
Diabetes Metab J. 2019;43(2):127-143.   Published online April 15, 2019
DOI: https://doi.org/10.4093/dmj.2019.0034
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AbstractAbstract PDFPubReader   ePub   

Nonalcoholic fatty liver disease (NAFLD) and diabetes are common metabolic disorders that are often comorbid conditions. Among many proposed treatments, weight reduction is the only approved option for NAFLD to date. However, it is not easy to maintain weight loss by lifestyle modification alone; pharmacological treatments are helpful in this regard. Although many drugs have been investigated, pioglitazone could be a first-line therapy in patients with NAFLD and diabetes. Many more drugs are currently being developed and investigated, and it is likely that combination strategies will be used for future treatment of NAFLD and diabetes. Attention should be paid to the management of NAFLD and diabetes and efforts should be made to intervene early and individualize treatment of NAFLD in patients with diabetes.

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Original Article
Clinical Diabetes & Therapeutics
Early Assessment of the Risk for Gestational Diabetes Mellitus: Can Fasting Parameters of Glucose Metabolism Contribute to Risk Prediction?
Veronica Falcone, Grammata Kotzaeridi, Melanie Hanne Breil, Ingo Rosicky, Tina Stopp, Gülen Yerlikaya-Schatten, Michael Feichtinger, Wolfgang Eppel, Peter Husslein, Andrea Tura, Christian S. Göbl
Diabetes Metab J. 2019;43(6):785-793.   Published online March 12, 2019
DOI: https://doi.org/10.4093/dmj.2018.0218
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AbstractAbstract PDFPubReader   ePub   
Background

An early identification of the risk groups might be beneficial in reducing morbidities in patients with gestational diabetes mellitus (GDM). Therefore, this study aimed to assess the biochemical predictors of glycemic conditions, in addition to fasting indices of glucose disposal, to predict the development of GDM in later stage and the need of glucose-lowering medication.

Methods

A total of 574 pregnant females (103 with GDM and 471 with normal glucose tolerance [NGT]) were included. A metabolic characterization was performed before 15+6 weeks of gestation by assessing fasting plasma glucose (FPG), fasting insulin (FI), fasting C-peptide (FCP), and glycosylated hemoglobin (HbA1c). Thereafter, the patients were followed-up until the delivery.

Results

Females with NGT had lower levels of FPG, FI, FCP, or HbA1c at the early stage of pregnancy, and therefore, showed an improved insulin action as compared to that in females who developed GDM. Higher fasting levels of FPG and FCP were associated with a higher risk of developing GDM. Moreover, the predictive accuracy of this metabolic profiling was also good to distinguish the patients who required glucose-lowering medications. Indices of glucose disposal based on C-peptide improved the predictive accuracy compared to that based on insulin. A modified quantitative insulin sensitivity check index (QUICKIc) showed the best differentiation in terms of predicting GDM (area under the receiver operating characteristics curve [ROC-AUC], 72.1%) or need for pharmacotherapy (ROC-AUC, 83.7%).

Conclusion

Fasting measurements of glucose and C-peptide as well as the surrogate indices of glycemic condition could be used for stratifying pregnant females with higher risk of GDM at the beginning of pregnancy.

Citations

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