Diabetes & Metabolism Journal

Basic and Translational Research
Interleukin 33 Promotes Liver Sinusoidal Endothelial Cell Dysfunction and Hepatic Fibrosis in Diabetic Mice: Huimin Chen, Chao Gao, Li Mo, Xingzhu Yin, Li Chen, Bangfu Wu, Ying Zhao, Xueer Cheng, Chanhua Liang, Bichao Xu, Dongyan Li, Yanyan Li, Ping Yao, Yuhan Tang; Received June 28, 2024 Accepted January 23, 2025 Published online May 22, 2025; DOI: https://doi.org/10.4093/dmj.2024.0532 [Epub ahead of print]

63 View
4 Download

Abstract PDF: Background
Interleukin 33 (IL33) drives liver fibrosis, and individuals with type 2 diabetes mellitus are more likely advanced to liver fibrosis. However, the role of IL33 in diabetic liver fibrosis remains unclear, prompting our investigation.
Methods
We developed a diabetes model in wild-type, IL33^−/−, and suppression of tumorigenicity 2 (ST2^−/−, IL33 receptor) mice. Furthermore, wild-type diabetic mice were injected with IL33 neutralizing antibody (αIL33). We also co-cultured human liver endothelial cells and human hepatic stellate cells to identify the role of IL33 in high palmitic acid and high glucose conditions.
Results
Hepatic collagen deposition was increased in diabetic mice, which was alleviated by IL33 knockout, ST2 knockout, or administration of αIL33. Also, αIL33 treatment blunted liver sinusoidal endothelial cell (LSEC) dysfunction and inflammation during diabetic liver fibrosis progression. Recombinant IL33 (rIL33) treatment aggravated autophagy disruption in the presence of palm acid and high glucose in LSECs, which was blunted by autophagy agonist rapamycin administration and ERK/MAPK inhibitor PD98059 treatment. Hepatic stellate cell line LX-2 co-cultured with rIL33-pretreated LSECs displayed augmented activation, which was also attenuated by rapamycin or PD98059 pretreated.
Conclusion
IL33 drives LSEC dysfunction and promotes diabetic hepatic fibrosis, thus a potential therapeutic target for diabetic liver fibrosis.

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]

71 View
4 Download

Abstract PDF: 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
Anti-Senescence Effect of Inhibiting Sodium-Glucose Cotransporter 2 and α-Glucosidase in a Type 2 Diabetes Mellitus Animal Model: Serin Hong, Byung Soo Kong, Hyunsuk Lee, Young Min Cho; Received June 28, 2024 Accepted January 23, 2025 Published online May 22, 2025; DOI: https://doi.org/10.4093/dmj.2024.0339 [Epub ahead of print]

94 View
13 Download

Abstract PDF: Background
The prevalence of type 2 diabetes mellitus (T2DM) increases with age, and cellular senescence of pancreatic β-cells plays a key role in T2DM pathogenesis. As canagliflozin and acarbose have been shown to increase lifespan in mice, we investigated the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitor, α-glucosidase inhibitor or both on the cellular senescence of β-cells in a T2DM mouse model.
Methods
Enavogliflozin (0.3 mg/kg), acarbose (10 mg/kg), or vehicle was orally administered daily to db/db mice for 6 weeks. The levels of senescence markers (p16, p21, and p53) in the pancreas and kidney were measured through real-time polymerase chain reaction (PCR), immunofluorescence staining, and Western blot. In an in vitro analysis, isolated pancreatic islets were exposed to H₂O₂ to induce cellular senescence, then treated with β-hydroxybutyrate (β-HB), and subsequently assessed for levels of senescent markers.
Results
Enavogliflozin alone or combined with acarbose effectively lowered blood glucose levels in db/db mice. The combined treatment resulted in the greatest increase in β-cell function calculated using insulinogenic index and homeostasis model assessment of β-cell function compared to the vehicle. Additionally, the combined treatment significantly reversed the increase in p16, with a similar trend observed in p21 and p53 in the islets. Treatment increased circulating β-HB and in vitro analysis suggested the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by β-HB in reducing senescence in the islets.
Conclusion
The combined administration of enavogliflozin and acarbose significantly reduced blood glucose, improved β-cell function, and reduced senescent β-cells in db/db mice. This combination therapy holds potential as a senotherapeutic strategy for managing T2DM.

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]

69 View
4 Download

Abstract PDF: 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.

Metabolic Risk/Epidemiology
Beta-Cell Function, Insulin Sensitivity, and Metabolic Characteristics in Young-Onset Type 2 Diabetes Mellitus: Findings from Anam Diabetes Observational Study: Ji Yoon Kim, Jiyoon Lee, Sin Gon Kim, Nam Hoon Kim; Received October 1, 2024 Accepted February 18, 2025 Published online May 21, 2025; DOI: https://doi.org/10.4093/dmj.2024.0601 [Epub ahead of print]

94 View
10 Download

Abstract PDF: Background
In this study, we aimed to determine the metabolic characteristics and changes in the early stages of young-onset type 2 diabetes mellitus (YOD) in Koreans.
Methods
From the Anam Diabetes Observational Study cohort (2017–2023), the characteristics of newly diagnosed YOD (<40 years of age, n=39) and later-onset (≥40 years of age) type 2 diabetes mellitus (LOD, n=178) were compared at diagnosis and 1 year later. All participants underwent an oral glucose tolerance test at diagnosis and annually thereafter. β-Cell function was determined using the disposition index (DI), calculated as the insulinogenic index×Matsuda insulin sensitivity index (ISI). Insulin sensitivity was determined using ISI and homeostasis model assessment of insulin resistance (HOMA2-IR).
Results
Mean (±standard deviation) age of individuals with YOD was 29.8±6.4 years, and 76.9% were male. YOD patients had higher body mass index (29.8 kg/m² vs. 27.2 kg/m², P=0.020), fat mass (30.5 kg vs. 24.1 kg, P=0.011), fatty liver index (65.4 vs. 49.2, P=0.005), and glycosylated hemoglobin (HbA1c) level at diagnosis (9.3% vs. 7.7%, P<0.001) compared with LOD patients. YOD patients exhibited lower insulin sensitivity (ISI: 2.79 vs. 3.26, P=0.008; HOMA2-IR: 2.72 vs. 1.83, P<0.001) and β-cell function (DI) at diagnosis (0.41 vs. 0.72, P=0.003) than LOD patients. Following 1 year of treatment, DI improved by 94% in YOD along with improvement in HbA1c; however, it was still significantly lower than that of LOD (0.64 vs. 0.90, P=0.017).
Conclusion
Individuals with YOD have unfavorable metabolic characteristics, substantially reduced insulin sensitivity, and decompensated β-cell function at disease onset, which persist even after treatment.

Complications
Impact of Remnant Cholesterol on the Risk for End-Stage Renal Disease in Type 2 Diabetes Mellitus: A Nationwide Population-Based Cohort Study: Eun Roh, Ji Hye Heo, Han Na Jung, Kyung-Do Han, Jun Goo Kang, Seong Jin Lee, Sung-Hee Ihm; Received July 21, 2024 Accepted January 23, 2025 Published online May 21, 2025; DOI: https://doi.org/10.4093/dmj.2024.0406 [Epub ahead of print]

105 View
5 Download

Abstract PDF: Background
Remnant cholesterol (remnant-C) has been linked to the risk of various vascular diseases, but the association between remnant-C and end-stage renal disease (ESRD) in patients with type 2 diabetes mellitus (T2DM) remains unclear.
Methods
Using a nationwide cohort, a total of 2,537,149 patients with T2DM without ESRD, who had participated in the national health screening in 2009, were enrolled and followed up until 2020. Low-density lipoprotein cholesterol (LDL-C) levels were assessed by the Martin-Hopkins method, and remnant-C was calculated as total cholesterol–LDL-C–high-density lipoprotein cholesterol.
Results
During a median follow-up period of 10.3 years, 26,246 patients with T2DM (1.03%) developed ESRD. Participants in the upper quartile of remnant-C had a higher risk of ESRD, with hazard ratios of 1.12 (95% confidence interval [CI], 1.08 to 1.17), 1.20 (95% CI, 1.15 to 1.24), and 1.33 (95% CI, 1.26 to 1.41) in the second, third, and fourth quartile, compared with the lowest quartile, in multivariable-adjusted analyses. The positive association between remnant-C and ESRD remained consistent, irrespective of age, sex, presence of pre-existing comorbidities, and use of anti-dyslipidemic medications. The increased risk of ESRD was more pronounced in high-risk subgroups, including those with hypertension, chronic kidney disease, obesity, and a longer duration of diabetes.
Conclusion
These findings suggest that remnant-C profiles in T2DM have a predictive role for future progression of ESRD, independent of traditional risk factors for renal dysfunction.

Metabolic Risk/Epidemiology
Predictive Models for Type 2 Diabetes Mellitus in Han Chinese with Insights into Cross-Population Applicability and Demographic Specific Risk Factors: Ying-Erh Chen, Djeane Debora Onthoni, Shao-Yuan Chuang, Guo-Hung Li, Yong-Sheng Zhuang, Hung-Yi Chiou, Wayne Huey-Herng Sheu, Ren-Hua Chung; Received June 20, 2024 Accepted January 6, 2025 Published online May 21, 2025; DOI: https://doi.org/10.4093/dmj.2024.0319 [Epub ahead of print]

144 View
9 Download

Abstract PDF: Background
The rising global incidence of type 2 diabetes mellitus (T2DM) underscores the need for predictive models that enhance early detection and prevention across diverse populations. This study aimed to identify predictors of incident T2DM within a Han Chinese population, assess their impact across various age and sex demographics, and explore their applicability to European populations.
Methods
Using data from about 65,000 participants in the Taiwan Biobank (TWB), we developed a predictive model, achieving an area under the receiver operating characteristic curve of 90.58%. Key predictors were identified through LASSO regression within the TWB cohort and validated using over 4 million records from Taiwan’s Adult Preventive Healthcare Services (APHS) program and the UK Biobank (UKB).
Results
Our analysis highlighted 13 significant predictors, including established factors like glycosylated hemoglobin (HbA1c) and blood glucose levels, and less conventionally considered variables such as peak expiratory flow. Notable differences in the effects of HbA1c levels and polygenic risk scores between the TWB and UKB cohorts were observed. Additionally, age and sex-specific impacts of these predictors, detailed through APHS data, revealed significant variances; for instance, waist circumference and diagnosed mixed hyperlipidemia showed greater impacts in younger females than in males, while effects remained uniform across male age groups.
Conclusion
Our findings offer novel insights into the diagnosis and management of diabetes for the Han Chinese and potentially for broader East Asian populations, highlighting the importance of ethnic and demographic diversity in developing predictive models for early detection and personalized intervention strategies.

Effects of Pancreatitis and Type 2 Diabetes Mellitus on the Development of Pancreatic Cancer: A Nationwide Nested Case-Control Study (Diabetes Metab J 2025;49:252-63): Young-eun Kim, Min Heui Yu, Chung Mo Nam, Eun Seok Kang; Diabetes Metab J. 2025;49(3):522-523. Published online May 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0314

256 View
9 Download

PDF PubReader ePub

Addressing the Persistent Increase and Inequities in Metabolically Unhealthy Obesity: Toward an Understanding of Clinical Obesity: Young Sang Lyu, Sang Yong Kim; Diabetes Metab J. 2025;49(3):405-406. Published online May 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0306

331 View
42 Download

PDF PubReader ePub

Efficacy and Safety of Automated Insulin Delivery Systems in Patients with Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis (Diabetes Metab J 2025;49:235-51): Wenqi Fan, Chao Deng, Zhiguang Zhou, Xia Li; Diabetes Metab J. 2025;49(3):520-521. Published online May 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0282

259 View
11 Download

PDF PubReader ePub

Advancing Early Prediction of Gestational Diabetes Mellitus with Circular RNA Biomarkers: Joon Ho Moon, Sung Hee Choi; Diabetes Metab J. 2025;49(3):403-404. Published online May 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0277

357 View
39 Download

PDF PubReader ePub

Critical Insights into the Efficacy and Safety of Automated Insulin Delivery Systems in Patients with Type 1 Diabetes Mellitus (Diabetes Metab J 2025;49:235-51): Sami Ullah, Ayesha Ahmad, Kamil Ahmad Kamil, Minahil Laraib Asif, Abdullah Jan; Diabetes Metab J. 2025;49(3):516-517. Published online May 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0243

254 View
16 Download

PDF PubReader ePub

Pancreatitis, Type 2 Diabetes Mellitus, and Pancreatic Cancer (Diabetes Metab J 2025;49:252-63): Shih-Wei Lai, Kuan-Fu Liao; Diabetes Metab J. 2025;49(3):518-519. Published online May 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0237

223 View
11 Download

PDF PubReader ePub

Pharmacotherapy
SGLT2 Inhibitors and GLP-1 Receptor Agonists in Diabetic Kidney Disease: Evolving Evidence and Clinical Application: Jae Hyun Bae; Diabetes Metab J. 2025;49(3):386-402. Published online May 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0220

1,858 View
368 Download

Abstract PDF PubReader ePub: Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease and significantly increases cardiovascular risk and mortality. Despite conventional therapies, including renin-angiotensin-aldosterone system inhibitors, substantial residual risk remains. The emergence of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists has reshaped DKD management. Beyond glycemic control, these agents provide distinct and complementary cardiorenal benefits through mechanisms such as hemodynamic modulation, anti-inflammatory effects, and metabolic adaptations. Landmark trials, including CREDENCE, DAPA-CKD, EMPA-KIDNEY, and FLOW, have demonstrated their efficacy in preserving kidney function and reducing adverse outcomes. SGLT2 inhibitors appear more effective in mitigating glomerular hyperfiltration and lowering heart failure risk, whereas GLP-1 receptor agonists are particularly beneficial in reducing albuminuria and atherosclerotic cardiovascular events. Although indirect comparisons suggest that SGLT2 inhibitors may offer greater protection against kidney function decline, direct head-to-head trials are lacking. Combination therapy holds promise, however further studies are needed to define optimal treatment strategies. This review synthesizes current evidence, evaluates comparative effectiveness, and outlines future directions in DKD management, emphasizing precision medicine approaches to enhance clinical outcomes. The integration of these therapies represents a paradigm shift in diabetes care, expanding treatment options for people with diabetes mellitus at risk of kidney failure.

Basic and Translational Research
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

426 View
50 Download

Abstract PDF PubReader 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.

Article category