Diabetes & Metabolism Journal

Review

Others
Differences between Type 2 Diabetes Mellitus and Obesity Management: Medical, Social, and Public Health Perspectives: Soo Lim, Ga Eun Nam, Arya M. Sharma; Received April 2, 2025 Accepted May 6, 2025 Published online June 11, 2025; DOI: https://doi.org/10.4093/dmj.2025.0278 [Epub ahead of print]

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Abstract PDF PubReader ePub: Obesity and type 2 diabetes mellitus (T2DM) are among the most urgent global public health challenges, yet differ markedly in recognition and management across medical, social, infrastructure, and policy domains. T2DM is supported by clear diagnostic criteria, defined treatment targets, and broad acceptance as a chronic disease. In contrast, obesity is assessed using imprecise metrics like body mass index, lacks standardized treatment goals, and is often misunderstood as a lifestyle issue rather than a chronic, relapsing disease. This misconception contributes to stigma, discrimination, and unrealistic patient expectations. T2DM receives substantial research funding, comprehensive clinical guidelines, and structured medical education, with strong support from large professional societies and multidisciplinary care models. Obesity care remains underfunded, inconsistently delivered, and underrepresented in medical training. Public health and policy efforts strongly favor T2DM, providing coordinated programs, insurance coverage, and regulatory oversight. Conversely, obesity is marginalized, with limited policy influence and a largely unregulated commercial weight-loss industry. Bridging these disparities requires adopting lessons from T2DM management—such as evidence-based guidelines, improved provider training, expanded insurance coverage, and public health strategies—to enhance obesity care and recognize it as a chronic disease requiring long-term, structured management.

Original Articles

Basic and Translational Research
Serpina3c Mitigates Adipose Tissue Inflammation by Inhibiting the HIF1α-Mediated Endoplasmic Reticulum Overoxidation in Adipocytes: Yu Jiang, Jia-Qi Guo, Ya Wu, Peng Zheng, Shao-Fan Wang, Meng-Chen Yang, Gen-Shan Ma, Yu-Yu Yao; Received July 31, 2024 Accepted February 25, 2025 Published online May 22, 2025; DOI: https://doi.org/10.4093/dmj.2024.0441 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Visceral white adipose tissue (vWAT) inflammation is a critical pathology of obesity-caused heart damage and is closely associated with adipocyte endoplasmic reticulum (ER) dysfunction. Serine (or cysteine) peptidase inhibitor, clade A, member 3C (Serpina3c) has been identified as an adipokine with anti-vWAT inflammatory effects. However, it remains unclear whether Serpina3c deficiency promotion of vWAT inflammation involves adipocyte ER dysfunction and whether it further contributes to heart damage in obesity.
Methods
Wild type and Serpina3c knockout (Serpina3c^–/–) mice were fed a high-fat diet (HFD) for 12 weeks. An adeno-associated virus (AAV) was injected locally into epididymal white adipose tissue (eWAT) of Serpina3c^–/– mice to induce eWAT-adipocyte- specific overexpression of Serpina3c (AAV-Serpina3c) or knockdown of hypoxia-inducible factor 1α (AAV-shHIF1α). In vitro experiments were performed in 3T3-L1 adipocytes.
Results
Serpina3c^–/– mice exhibited more severe eWAT, serum and heart inflammation after HFD feeding. Consistently, these adverse phenotypes were mitigated in AAV-Serpina3c and AAV-shHIF1α mice. Mechanistically, ER oxidoreductase 1α (Ero1α) and protein disulfide isomerase (PDI) family members PDIA3 and PDIA4 were found to be target genes of HIF1α. In the obese mice, Serpina3c deficiency caused adipocyte more hypertrophy, and activated HIF1α-Ero1α/PDI mediated ER overoxidation and ER stress in eWAT. Subsequently, this led to increased adipocyte apoptosis and chemokine production and decreased adiponectin expression, which promoted macrophage infiltration and M1 polarization in eWAT, thus exacerbating eWAT inflammation and ultimately facilitating serum and distal heart inflammation.
Conclusion
These findings indicate that Serpina3c is a significant regulator of adipocyte ER redox homeostasis, thus highlighting Serpina3c as a potential therapeutic target for obesity-related eWAT inflammation and heart damage.

Basic and Translational Research
Phosphodiesterase 5 Inhibitor Improves Insulin Sensitivity by Regulating Adipose Tissue Macrophage Polarization in Diet-Induced Obese Mice: Dan-Gyeong Song, Seongwon Pak, Dae-Chul Shin, Shindy Soedono, Kae Won Cho, Yejin Park, Subin Moon, Sooyeon Jang, Saeha Kim, Sang-Won Han, Keunwook Lee, Jong-Hee Sohn, Chan Hee Lee; Received June 14, 2024 Accepted February 25, 2025 Published online May 22, 2025; DOI: https://doi.org/10.4093/dmj.2024.0308 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Obesity is a rapidly increasing global health issue, which is associated with glucose and insulin resistance. Phosphodiesterase type 5 (PDE5) inhibitors (PDE5i) are known for their ability to enhance blood flow and vascular stability and are widely used to treat conditions such as erectile dysfunction, pulmonary hypertension, heart failure, and cancer. However, studies investigating the role of PDE5i in alleviating obesity and metabolic diseases remains unclear. Therefore, we investigated the effects of PDE5i on obesity and metabolic disorders in diet-induced obese mice and its underlying mechanisms.
Methods
PDE5i was administered to high-fat diet (HFD)-fed C57BL/6J mice for 6 to 7 weeks. Body weight and food intake were measured weekly, and baseline metabolic rates, physical activity, and glucose and insulin tolerance tests were assessed during PDE5i administration. Macrophages and T-cells in the gonadal white adipose tissue (gWAT) were analyzed by flow cytometry. Vascular stability and blood flow in gWAT were analyzed via immunostaining and in vivo live imaging. RAW264.7 cells and bone marrow-derived macrophages were used to determine immunoregulatory effects of PDE5i.
Results
In HFD-fed mice, PDE5i administration significantly enhanced systemic insulin sensitivity and AKT phosphorylation in gWAT. PDE5i reduced the M1/M2 ratio of gWAT macrophages of obese mice. These phenomena were associated with enhanced blood flow to the gWAT. In vitro experiments revealed that PDE5i suppressed lipopolysaccharide-induced proinflammatory cytokine production and increased the mRNA expression of genes associated with M2 polarization.
Conclusion
PDE5i plays a role in regulating adipose tissue inflammation and thus holds promise as a therapeutic agent for metabolic enhancement.

Reviews

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.

Basic and Translational Research
Glucagon-Like Peptide-1 and Hypothalamic Regulation of Satiation: Cognitive and Neural Insights from Human and Animal Studies: Joon Seok Park, Kyu Sik Kim, Hyung Jin Choi; Diabetes Metab J. 2025;49(3):333-347. Published online May 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0106

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Abstract PDF PubReader ePub: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as blockbuster drugs for treating metabolic diseases. Glucagon-like peptide-1 (GLP-1) plays a pivotal role in glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and acting on the central nervous system to regulate satiation and satiety. This review summarizes the discovery of GLP-1 and the development of GLP-1RAs, with a particular focus on their central mechanisms of action. Human neuroimaging studies demonstrate that GLP-1RAs influence brain activity during food cognition, supporting a role in pre-ingestive satiation. Animal studies on hypothalamic feed-forward regulation of hunger suggest that cognitive hypothalamic mechanisms may also contribute to satiation control. We highlight the brain mechanisms of GLP-1RA-induced satiation and satiety, including cognitive impacts, with an emphasis on animal studies of hypothalamic glucagon-like peptide-1 receptor (GLP-1R) and GLP-1R-expressing neurons. Actions in non-hypothalamic regions are also discussed. Additionally, we review emerging combination drugs and oral GLP-1RA formulations aimed at improving efficacy and patient adherence. In conclusion, the dorsomedial hypothalamus (DMH)—a key GLP-1RA target—mediates pre-ingestive cognitive satiation, while other hypothalamic GLP-1R neurons regulate diverse aspects of feeding behavior, offering potential therapeutic targets for obesity treatment.

Original Articles

Basic Research
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; Received August 17, 2024 Accepted October 23, 2024 Published online March 11, 2025; DOI: https://doi.org/10.4093/dmj.2024.0486 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader 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.

Guideline/Statement/Fact Sheet
Prevalence, Incidence, and Metabolic Characteristics of Young Adults with Type 2 Diabetes Mellitus in South Korea (2010–2020): Ji Yoon Kim, Jiyoon Lee, Joon Ho Moon, Se Eun Park, Seung-Hyun Ko, Sung Hee Choi, Nam Hoon Kim; Diabetes Metab J. 2025;49(2):172-182. Published online March 1, 2025; DOI: https://doi.org/10.4093/dmj.2024.0826

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Abstract PDF Supplementary Material PubReader ePub: Background
This study aimed to examine trends in the prevalence, incidence, metabolic characteristics, and management of type 2 diabetes mellitus (T2DM) among young adults in South Korea.
Methods
Young adults with T2DM were defined as individuals aged 19 to 39 years who met the diagnostic criteria for T2DM. Data from the Korean National Health Insurance Service-Customized Database (2010–2020, n=225,497–372,726) were analyzed to evaluate trends in T2DM prevalence, incidence, metabolic profiles, comorbidities, and antidiabetic drug prescription. Additional analyses were performed using the Korea National Health and Nutrition Examination Survey.
Results
The prevalence of T2DM in young adults significantly increased from 1.02% in 2010 to 2.02% in 2020 (P<0.001), corresponding to 372,726 patients in 2020. Over the same period, the incidence rate remained stable within the range of 0.36% to 0.45%. Prediabetes prevalence steadily increased from 15.53% to 20.92%, affecting 3.87 million individuals in 2020. The proportion of young adults with T2DM who were obese also increased, with 67.8% having a body mass index (BMI) ≥25 kg/m² and 31.6% having a BMI ≥30 kg/m² in 2020. The prevalence of hypertension, dyslipidemia, and fatty liver disease also increased, reaching 34.2%, 79.8%, and 78.9%, respectively, in 2020. Although the overall pharmacological treatment rate remained low, the prescription of antidiabetic medications with weight-reducing properties increased over the study period.
Conclusion
The prevalence of T2DM among young adults in South Korea nearly doubled over the past decade. The strong association with obesity and metabolic comorbidities emphasizes the urgent need for targeted prevention and management strategies tailored to this population.

Metabolic Risk/Epidemiology
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

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Abstract PDF Supplementary Material PubReader 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

Citations to this article as recorded by

Addressing the Persistent Increase and Inequities in Metabolically Unhealthy Obesity: Toward an Understanding of Clinical Obesity
Young Sang Lyu, Sang Yong Kim
Diabetes & Metabolism Journal.2025; 49(3): 405. CrossRef
Liver and obesity: a narrative review
Amedeo Lonardo, Ralf Weiskirchen
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Cardiovascular Risk/Epidemiology
Normalized Creatinine-to-Cystatin C Ratio and Risk of Cardiometabolic Multimorbidity in Middle-Aged and Older Adults: Insights from the China Health and Retirement Longitudinal Study: Honglin Sun, Zhenyu Wu, Guang Wang, Jia Liu; Diabetes Metab J. 2025;49(3):448-461. Published online January 20, 2025; DOI: https://doi.org/10.4093/dmj.2024.0100

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Abstract PDF Supplementary Material PubReader ePub: Background
Normalized creatinine-to-cystatin C ratio (NCCR) was reported to approximate relative skeletal muscle mass and diabetes risk. However, the association between NCCR and cardiometabolic multimorbidity (CMM) remains elusive. This study aimed to explore their relationship in a large-scale prospective cohort.
Methods
This study included 5,849 middle-age and older participants from the China Health and Retirement Longitudinal Study (CHARLS) enrolled between 2011 and 2012. The baseline NCCR was determined as creatinine (mg/dL)/cystatin C (mg/L)×10/body mass (kg). CMM was defined as the simultaneous occurrence of two or more of the following conditions: heart disease, stroke, and type 2 diabetes mellitus. Logistic regression analysis and Cox regression analysis were employed to estimate the relationship between NCCR and CMM. The joint effect of body mass index and NCCR on the risk of CMM were further analyzed.
Results
During a median 4-year follow-up, 227 (3.9%) participants developed CMM. The risk of CMM was significantly decreased with per standard deviation increase of NCCR (odds ratio, 0.72; 95% confidence interval, 0.62 to 0.85) after adjustment for confounders (P<0.001). Further sex-specific analysis found significant negative associations between NCCR and CMM in female either without or with one CMM component at baseline, which was attenuated in males but remained statistically significant among those with one basal CMM component. Notably, non-obese individuals with high NCCR levels had the lowest CMM risk compared to obese counterparts with low NCCR levels in both genders.
Conclusion
High NCCR was independently associated with reduced risk of CMM in middle-aged and older adults in China, particularly females.

Others
Serum Magnesium Levels Are Negatively Associated with Obesity and Abdominal Obesity in Type 2 Diabetes Mellitus: A Real-World Study: Man-Rong Xu, Ai-Ping Wang, Yu-Jie Wang, Jun-Xi Lu, Li Shen, Lian-Xi Li; Diabetes Metab J. 2024;48(6):1147-1159. Published online May 29, 2024; DOI: https://doi.org/10.4093/dmj.2023.0401

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Abstract PDF Supplementary Material PubReader ePub

Background
There remains controversy over the relationship between serum magnesium levels and obesity in type 2 diabetes mellitus (T2DM). Therefore, the aim of this study was to assess whether there is any association of serum magnesium levels with obesity and abdominal obesity in T2DM.
Methods
This cross-sectional, real-world study was conducted in 8,010 patients with T2DM, which were stratified into quintiles according to serum magnesium levels. The clinical characteristics and the prevalence of obesity and abdominal obesity were compared across serum magnesium quintiles in T2DM. Regression analyses were used to evaluate the relationship of serum magnesium with obesity and abdominal obesity in T2DM (clinical trial registration number: ChiCTR1800015893).
Results
After adjustment for age, sex, and duration of diabetes, the prevalence of obesity and abdominal obesity was significantly declined across magnesium quintiles (obesity: 51.3%, 50.8%, 48.9%, 45.3%, and 43.8%, respectively, P<0.001 for trend; abdominal obesity: 71.5%, 70.5%, 68.2%, 66.4%, and 64.5%, respectively, P=0.001 for trend). After controlling for confounders, there were clearly negative associations of serum magnesium levels and quintiles with obesity and abdominal obesity in T2DM. Moreover, C-reactive protein partly mediates the effect of serum magnesium on obesity and abdominal obesity (P=0.016 and P=0.004, respectively).
Conclusion
The significantly negative relationship between serum magnesium and the risk of obesity and abdominal obesity was observed in T2DM. Furthermore, the independently negative association of serum magnesium with obesity may be explained by its anti-inflammatory functions. Serum magnesium levels may be applied to assess the risk of obesity and abdominal obesity in T2DM.

Citations

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Electrolyte Imbalances and Metabolic Emergencies in Obesity: Mechanisms and Clinical Implications
Iulia Najette Crintea, Alexandru Cristian Cindrea, Ovidiu Alexandru Mederle, Cosmin Iosif Trebuian, Romulus Timar
Diseases.2025; 13(3): 69. CrossRef
Magnesium Matters: A Comprehensive Review of Its Vital Role in Health and Diseases
Ghizal Fatima, Andrej Dzupina, Hekmat B Alhmadi, Aminat Magomedova, Zainab Siddiqui, Ammar Mehdi, Najah Hadi
Cureus.2024;[Epub] CrossRef

Reviews

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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Abstract PDF PubReader ePub

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.

Citations

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Pathophysiology
Dysfunctional Mitochondria Clearance in Situ: Mitophagy in Obesity and Diabetes-Associated Cardiometabolic Diseases: Songling Tang, Di Hao, Wen Ma, Lian Liu, Jiuyu Gao, Peng Yao, Haifang Yu, Lu Gan, Yu Cao; Diabetes Metab J. 2024;48(4):503-517. Published online February 15, 2024; DOI: https://doi.org/10.4093/dmj.2023.0213

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Several mitochondrial dysfunctions in obesity and diabetes include impaired mitochondrial membrane potential, excessive mitochondrial reactive oxygen species generation, reduced mitochondrial DNA, increased mitochondrial Ca²⁺ flux, and mitochondrial dynamics disorders. Mitophagy, specialized autophagy, is responsible for clearing dysfunctional mitochondria in physiological and pathological conditions. As a paradox, inhibition and activation of mitophagy have been observed in obesity and diabetes-related heart disorders, with both exerting bidirectional effects. Suppressed mitophagy is beneficial to mitochondrial homeostasis, also known as benign mitophagy. On the contrary, in most cases, excessive mitophagy is harmful to dysfunctional mitochondria elimination and thus is defined as detrimental mitophagy. In obesity and diabetes, two classical pathways appear to regulate mitophagy, including PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent mitophagy and receptors/adapters-dependent mitophagy. After the pharmacologic interventions of mitophagy, mitochondrial morphology and function have been restored, and cell viability has been further improved. Herein, we summarize the mitochondrial dysfunction and mitophagy alterations in obesity and diabetes, as well as the underlying upstream mechanisms, in order to provide novel therapeutic strategies for the obesity and diabetes-related heart disorders.

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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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Original Articles

Basic Research
Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition: Ho Gyun Lee, Il Hyeon Jung, Byong Seo Park, Hye Rim Yang, Kwang Kon Kim, Thai Hien Tu, Jung-Yong Yeh, Sewon Lee, Sunggu Yang, Byung Ju Lee, Jae Geun Kim, Il Seong Nam-Goong; Diabetes Metab J. 2023;47(6):784-795. Published online August 23, 2023; DOI: https://doi.org/10.4093/dmj.2022.0261

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Background
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are currently used to treat patients with diabetes. Previous studies have demonstrated that treatment with SGLT-2 inhibitors is accompanied by altered metabolic phenotypes. However, it has not been investigated whether the hypothalamic circuit participates in the development of the compensatory metabolic phenotypes triggered by the treatment with SGLT-2 inhibitors.
Methods
Mice were fed a standard diet or high-fat diet and treated with dapagliflozin, an SGLT-2 inhibitor. Food intake and energy expenditure were observed using indirect calorimetry system. The activity of hypothalamic neurons in response to dapagliflozin treatment was evaluated by immunohistochemistry with c-Fos antibody. Quantitative real-time polymerase chain reaction was performed to determine gene expression patterns in the hypothalamus of dapagliflozin-treated mice.
Results
Dapagliflozin-treated mice displayed enhanced food intake and reduced energy expenditure. Altered neuronal activities were observed in multiple hypothalamic nuclei in association with appetite regulation. Additionally, we found elevated immunosignals of agouti-related peptide neurons in the paraventricular nucleus of the hypothalamus.
Conclusion
This study suggests the functional involvement of the hypothalamus in the development of the compensatory metabolic phenotypes induced by SGLT-2 inhibitor treatment.

Citations

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Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition (Diabetes Metab J 2023;47:784-95)
Jae Hyun Bae
Diabetes & Metabolism Journal.2024; 48(1): 157. CrossRef
Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition (Diabetes Metab J 2023;47:784-95)
Ho Gyun Lee, Il Hyeon Jung, Byong Seo Park, Hye Rim Yang, Kwang Kon Kim, Thai Hien Tu, Jung-Yong Yeh, Sewon Lee, Sunggu Yang, Byung Ju Lee, Jae Geun Kim, Il Seong Nam-Goong
Diabetes & Metabolism Journal.2024; 48(1): 159. CrossRef

Metabolic Risk/Epidemiology
Differential Impact of Obesity on the Risk of Diabetes Development in Two Age Groups: Analysis from the National Health Screening Program: Tae Kyung Yoo, Kyung-Do Han, Yang-Hyun Kim, Ga Eun Nam, Sang Hyun Park, Eun-Jung Rhee, Won-Young Lee; Diabetes Metab J. 2023;47(6):846-858. Published online August 23, 2023; DOI: https://doi.org/10.4093/dmj.2022.0242

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Background
The effect of obesity on the development of type 2 diabetes mellitus (DM) in different age groups remains unclear. We assessed the impact of obesity on the development of DM for two age groups (40-year-old, middle age; 66-year-old, older adults) in the Korean population.
Methods
We analyzed Korean National Health Insurance Service data of 4,145,321 Korean adults with 40- and 66-year-old age without DM, between 2009 and 2014. Participants were followed up until 2017 or until the diagnosis of DM. We assessed the risk of DM based on the body mass index and waist circumference of the participants. Multiple confounding factors were adjusted.
Results
The median follow-up duration was 5.6 years. The association of general and abdominal obesity with the risk of DM development was stronger in the 40-year-old group (general obesity: hazard ratio [HR], 3.566, 95% confidence interval [CI], 3.512 to 3.622; abdominal obesity: HR, 3.231; 95% CI, 3.184 to 3.278) than in the 66-year-old group (general obesity: HR, 1.739; 95% CI, 1.719 to 1.759; abdominal obesity: HR, 1.799; 95% CI, 1.778 to 1.820). In the 66-year-old group, abdominal obesity had a stronger association with the development of DM as compared to general obesity. In the 40-year-old group, general obesity had a stronger association with the risk of DM development than abdominal obesity.
Conclusion
The influence of general and abdominal obesity on the development of DM differed according to age. In older adults, abdominal obesity had a stronger association with DM development than general obesity.

Citations

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Age at Menopause and Development of Type 2 Diabetes in Korea
Byung-Joon Ko, Jin-Hyung Jung, Kyungdo Han, Ga Eun Nam
JAMA Network Open.2025; 8(1): e2455388. CrossRef
Association of Body Composition Changes with the Development of Diabetes Mellitus: A Nation-Wide Population Study
Hyung Jun Kim, Hyung-Woo Lee, Min-Kyoung Kang, Gwang Hyun Leem, Min-Ho Kim, Tae-Jin Song
Diabetes & Metabolism Journal.2024; 48(6): 1093. CrossRef

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