Diabetes & Metabolism Journal

Original Articles

Genetics
SLC30A8 Rare Variant Modify Contribution of Common Genetic and Lifestyle Factors toward Type 2 Diabetes Mellitus: Hye-Mi Jang, Mi Yeong Hwang, Yi Seul Park, Bong-Jo Kim, Young Jin Kim; Diabetes Metab J. 2026;50(2):385-395. Published online August 13, 2025; DOI: https://doi.org/10.4093/dmj.2024.0830

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Background
This study aimed to investigate the modifying effects of rare genetic variants on the risk of type 2 diabetes mellitus (T2DM) in the context of common genetic and lifestyle factors.
Methods
We conducted a comprehensive analysis of genetic and lifestyle factors associated with T2DM in a cohort of 146,284 Korean individuals. Among them, 4,603 individuals developed T2DM during the follow-up period of up to 17 years. We calculated a polygenic risk score (PRS) for T2DM and identified carriers of the rare allele I349F at SLC30A8. A Healthy Lifestyle Score (HLS) was also derived from physical activity, obesity, smoking, diet, and sodium intake levels. Using Cox proportional hazards models, we analyzed how PRS, HLS, and I349F influenced T2DM incidence.
Results
Results showed that high PRS and poor lifestyle were associated with increased risk. Remarkably, I349F carriers exhibited a lower T2DM prevalence (5.7% compared to 11.7% in non-carriers) and reduced the impact of high PRS from 23.18% to 12.70%. This trend was consistent across different HLS categories, with I349F carriers displaying a lower risk of T2DM.
Conclusion
The integration of common and rare genetic variants with lifestyle factors enhanced T2DM predictability in the Korean population. Our findings highlight the critical role of rare genetic variants in risk assessments and suggest that standard PRS and HLS metrics alone may be inadequate for predicting T2DM risk among carriers of such variants.

Citations

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Personalised Nutrition in Obesity and Prediabetes: Do Genotypes Matter?
Magdalena Bossowska, Filip Bossowski, Edyta Adamska-Patruno, Katarzyna Maliszewska, Adam Krętowski
Nutrients.2026; 18(5): 815. CrossRef
Differential contributions of cardiovascular health-related lifestyle factors to epigenetic ageing: implications for healthy longevity
Da-eun Lee, Yi Seul Park, Hye-Mi Jang, Bong-Jo Kim, Young Jin Kim, Sung-il Cho, Kyeezu Kim
BMC Medicine.2025;[Epub] CrossRef

Metabolic Risk/Epidemiology
Birth Weight, Cardiovascular Health, and Microvascular Complications in Individuals with Diabetes Mellitus: Chaolun Yu, Anping Feng, Xia Zou, Siqi Chen, Lingyan Dai, Qingmei Cui, Xiaojing Kuang, Gaoli She, Ying Ma, Haixia Guan, Jie Li; Diabetes Metab J. 2025;49(5):1075-1086. Published online May 23, 2025; DOI: https://doi.org/10.4093/dmj.2024.0518

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Abstract PDF Supplementary Material PubReader ePub: Background
Diabetes often leads to microvascular complications, including nephropathy, neuropathy, and retinopathy. Understanding the impact of early-life factors like birth weight and modifiable behaviors such as cardiovascular health (CVH) is essential for preventing these complications.
Methods
We included 11,515 participants with diabetes but without microvascular complications at baseline from the UK Biobank Study. CVH was evaluated using the Life’s Essential 8 score. Independent and joint associations of birth weight and CVH with microvascular complications were analyzed using Cox proportional hazard models. Two-sample Mendelian randomization (MR) analyses estimated unconfounded associations between birth weight and microvascular complications.
Results
Over a median follow-up of 13.1 years, 3,010 microvascular complications occurred. Compared with normal birth weight (2.5–4.0 kg), low birth weight (LBW; <2.5 kg) was associated with 15% higher risk of diabetic nephropathy (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.01 to 1.31), but not with neuropathy and retinopathy. High birth weight (>4.0 kg) was not associated with the risk of diabetic microvascular complications. MR analysis confirmed the association between LBW and nephropathy. Adherence to high CVH was associated with a reduced risk of microvascular complications compared to low CVH, regardless of birth weight. The HRs were 0.70 (95% CI, 0.59 to 0.84) for the LBW group and 0.74 (95% CI, 0.68 to 0.80) for the group with birth weight ≥2.5 kg (P for interaction=0.69).
Conclusion
LBW was an independent risk factor for nephropathy among diabetic patients. However, the detrimental effects of LBW might be mitigated by improvement in CVH.

Lifestyle and Behavioral Interventions
Association between Healthy Lifestyle Factors and Metabolic Syndrome Risk: A Prospective Analysis of the Korean Genome and Epidemiology Study: Jialei Fu, Sangah Shin; Diabetes Metab J. 2025;49(4):873-882. Published online March 26, 2025; DOI: https://doi.org/10.4093/dmj.2024.0427

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Abstract PDF Supplementary Material PubReader ePub: Background
To investigate the association of adherence to five modifiable lifestyle factors (limiting alcohol, physical activity, limiting smoking, favorable diet quality, and adequate sleep) with metabolic syndrome (MetS) risk in Korean adults.
Methods
Health Examinees Study data were used, and 41,368 participants aged 40 to 69 years were included. Cox proportional hazards regression analyses assessed the associations of individual and combined healthy lifestyle factors (32 and 16 lifestyle profiles in men and women.
Results
During a median 4.2-year follow-up, 6,213 participants were newly diagnosed with MetS. Adherence to more healthy lifestyle factors (4–5 vs. 0–1) could lower MetS risk by 28% and 12% in men and women (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.63 to 0.83 in men; HR, 0.88; 95% CI, 0.78 to 0.99 in women). Each additional healthy lifestyle could reduce the risk of MetS by 10% and 6% in men and women. The pooled analysis yielded similar results based on similar numbers of healthy lifestyle factors, the risk of MetS decreased as the number of healthy lifestyle factors increased.
Conclusion
Adherence to more healthy lifestyle factors was inversely associated with MetS risk. These findings highlight the importance of limiting drinking in managing MetS. Future research should consider the synergistic effects of emerging lifestyle factors, such as sleep duration, on chronic disease development, while focusing on the effects of traditional lifestyle factors.

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.

Citations

Citations to this article as recorded by

The Role of Kupffer Cells and Liver Macrophages in the Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease
Ioannis Tsomidis, Angeliki Tsakou, Argyro Voumvouraki, Elias Kouroumalis
Biomedicines.2026; 14(1): 151. CrossRef
Impact of healthy lifestyles on the risk of metabolic dysfunction‐associated steatotic liver disease among adults with comorbid hypertension and diabetes: Novel insight from a largely middle‐aged and elderly cohort in South China
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
Diabetes, Obesity and Metabolism.2025; 27(5): 2800. CrossRef
Cholesteryl ester transfer protein gene variants and metabolic dysfunction-associated steatotic liver disease: genetic associations with steatosis in obese and lean individuals
Asmaa AbdelFattah, Mahmoud Kattab, Hosny Abdel Ghany, Lamiaa Aly, Ahmed Mady, Aly Hamdi, Riham Soliman, Gamal Shiha, Nada El-Domiaty
Egyptian Liver Journal.2025;[Epub] CrossRef
Research trends on the quality of life in patients with metabolic dysfunction-associated fatty liver diseases: a scientific metrology study
Can Huang, Meng Chen, Yanfang Sun, Lin Zhang, Wei Liu
Frontiers in Nutrition.2025;[Epub] CrossRef
The relationship between tobacco and non-alcoholic fatty liver disease incidence: a systematic review and meta-analysis of observational studies
Jianxiang Jin, Yuping Zhang, Yiping Huang
Frontiers in Medicine.2025;[Epub] CrossRef
Enhancing MAFLD Care: Efficacy of a Multidisciplinary Community Intervention on Self-Management and Hepatic Outcomes
Huan-Jing Cai, Hai-Lun Liang, Lei-Yu Shi, Yi-Hui Rong, Jing Li, Yan Zhang, Rui-Fang Ma
INQUIRY: The Journal of Health Care Organization, Provision, and Financing.2025;[Epub] CrossRef
Mechanistic investigation of DDT/DDE in MASLD/MASH pathogenesis: An integrated network toxicology and transcriptomics approach
Yicheng Jiang, Yuancheng Shao, Jiaming Xue, Zhigang Chen, Qi Liu, Shuai Chen, Xihan Gu, Shufan Zhang, Liming Tang
Ecotoxicology and Environmental Safety.2025; 307: 119390. CrossRef
Multiorgan crosstalk in MASLD/MASH: from hepatic pathogenesis to systemic complications
Wenhua Bai, Zheng Zhu
Frontiers in Endocrinology.2025;[Epub] CrossRef
Diagnostic indicators and lifestyle interventions of metabolic-associated fatty liver disease
Tianzhu Chen, Xiang Qin, Jianping Jiang, Beihui He
Frontiers in Nutrition.2024;[Epub] CrossRef
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
Frontiers in Medicine.2024;[Epub] CrossRef
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
Nutrition & Diabetes.2024;[Epub] CrossRef

Review

Others
Mitochondrial Toxins and Healthy Lifestyle Meet at the Crossroad of Hormesis: Yu-Mi Lee, Duk-Hee Lee; Diabetes Metab J. 2019;43(5):568-577. Published online October 24, 2019; DOI: https://doi.org/10.4093/dmj.2019.0143

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Mitochondrial function is crucial for the maintenance of cellular homeostasis under physiological and stress conditions. Thus, chronic exposure to environmental chemicals that affect mitochondrial function can have harmful effects on humans. We argue that the concept of hormesis should be revisited to explain the non-linear responses to mitochondrial toxins at a low-dose range and develop practical methods to protect humans from the negative effects of mitochondrial toxins. Of the most concern to humans are lipophilic chemical mixtures and heavy metals, owing to their physical properties. Even though these chemicals tend to demonstrate no safe level in humans, a non-linear dose-response has been also observed. Stress response activation, i.e., hormesis, can explain this non-linearity. Recently, hormesis has reemerged as a unifying concept because diverse stressors can induce similar stress responses. Besides potentially harmful environmental chemicals, healthy lifestyle interventions such as exercise, calorie restriction (especially glucose), cognitive stimulation, and phytochemical intake also activate stress responses. This conceptual link can lead to the development of practical methods that counterbalance the harm of mitochondrial toxins. Unlike chemical hormesis with its safety issues, the activation of stress responses via lifestyle modification can be safely used to combat the negative effects of mitochondrial toxins.

Citations

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Polyethylene terephthalate (PET) micro- and nanoplastic particles affect the mitochondrial efficiency of human brain vascular pericytes without inducing oxidative stress
Sean M. Gettings, William Timbury, Anna Dmochowska, Riddhi Sharma, Rebecca McGonigle, Lewis E. MacKenzie, Guillaume Miquelard-Garnier, Nora Bourbia
NanoImpact.2024; 34: 100508. CrossRef
The current insights of mitochondrial hormesis in the occurrence and treatment of bone and cartilage degeneration
Wacili Da, Quan Chen, Bin Shen
Biological Research.2024;[Epub] CrossRef
Neurodegenerative disorders, metabolic icebergs, and mitohormesis
Matthew C. L. Phillips, Martin Picard
Translational Neurodegeneration.2024;[Epub] CrossRef
Mitochondrial Dysfunction and Risk Factors for Noncommunicable Diseases: From Basic Concepts to Future Prospective
Ganna Nevoit, Gediminas Jarusevicius, Maksim Potyazhenko, Ozar Mintser, Inga Arune Bumblyte, Alfonsas Vainoras
Diseases.2024; 12(11): 277. CrossRef
Rules of Heliogeomagnetics Diversely Coordinating Biological Rhythms and Promoting Human Health
Kuniaki Otsuka, Germaine Cornelissen, Andi Weydahl, Denis Gubin, Larry A. Beaty, Masatoshi Murase
Applied Sciences.2023; 13(2): 951. CrossRef
Can lipophilic pollutants in adipose tissue explain weight change‐related risk in type 2 diabetes mellitus?
Duk‐Hee Lee, In‐Kyu Lee
Journal of Diabetes Investigation.2023; 14(4): 528. CrossRef
Hormetic Effects of Cerium, Lanthanum and Their Combination at Sub-micromolar Concentrations in Sea Urchin Sperm
Giovanni Pagano, Antonios Apostolos Brouziotis, Daniel Lyons, Ivana Čarapar, Rahime Oral, Serkan Tez, Philippe J. Thomas, Franca Tommasi, Giovanni Libralato, Marco Guida, Marco Trifuoggi
Bulletin of Environmental Contamination and Toxicology.2023;[Epub] CrossRef
Mitochondria: It is all about energy
Amaloha Casanova, Anne Wevers, Santiago Navarro-Ledesma, Leo Pruimboom
Frontiers in Physiology.2023;[Epub] CrossRef
Type 2 Diabetes Induced by Changes in Proteomic Profiling of Zebrafish Chronically Exposed to a Mixture of Organochlorine Pesticides at Low Concentrations
Yan Gao, Hyojin Lee, Sangkyu Lee, Ki-Tae Kim
International Journal of Environmental Research and Public Health.2022; 19(9): 4991. CrossRef
Effect of Low-Dose Persistent Organic Pollutants on Mitochondrial Function: Human and in Vitro Evidence
Se-A Kim, Hoyul Lee, Sung-Mi Park, Mi-Jin Kim, Yu-Mi Lee, Young-Ran Yoon, Hyun-Kyung Lee, Hyo-Bang Moon, In-Kyu Lee, Duk-Hee Lee
Diabetes & Metabolism Journal.2022; 46(4): 592. CrossRef
Can Environmental Pollutants Be a Factor Linking Obesity and COVID-19?
Duk-Hee Lee
Journal of Korean Medical Science.2021;[Epub] CrossRef
Intensive weight loss and cognition: The dynamics of persistent organic pollutants in adipose tissue can explain the unexpected results from the Action for Health in Diabetes (Look AHEAD) study
Yu‐Mi Lee, Sun‐Hee Park, Duk‐Hee Lee
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Lipophilic Environmental Chemical Mixtures Released During Weight‐Loss: The Need to Consider Dynamics
Duk‐Hee Lee, David R Jacobs, Lars Lind, P. Monica Lind
BioEssays.2020;[Epub] CrossRef
Environmental toxicology and ecotoxicology: How clean is clean? Rethinking dose-response analysis
Evgenios Agathokleous, Edward J. Calabrese
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