Diabetes & Metabolism Journal

Articles in E-pub version are posted online ahead of regular printed publication.

Original Articles

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]

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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]

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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]

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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]

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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]

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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]

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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]

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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.

Pharmacotherapy
Initial Pharmacological Strategies in People with Early Type 2 Diabetes Mellitus: A Systematic Review and Network Meta-Analysis: Jong Han Choi, Bo Kyung Koo, Ye Seul Yang, Se Hee Min, Jong Suk Park, Sang Youl Rhee, Hyun Jung Kim, Min Kyong Moon; Received October 24, 2024 Accepted January 16, 2025 Published online April 29, 2025; DOI: https://doi.org/10.4093/dmj.2024.0660 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Type 2 diabetes mellitus (T2DM) requires stringent glycemic control from an early stage to prevent complications. The most effective treatment regimen for early T2DM remains unclear. The study aimed to compare the efficacy and safety of monotherapies and combination therapies for early T2DM.
Methods
A systematic review and network meta-analysis were conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Randomized controlled trials focused on glycemic control, body weight, and adverse events were included. The primary outcomes were changes in glycosylated hemoglobin (HbA1c) and odds of achieving the target HbA1c after 6 months.
Results
All combination therapies were more effective than monotherapy. Metformin+glucagon-like peptide-1 receptor agonists (GLP-1RA) (weighted mean difference [WMD] –1.50%; 95% confidence interval [CI] –2.04 to –0.96) and metformin+dipeptidyl peptidase-4 inhibitors (WMD –1.46%; 95% CI, –1.96 to –0.95) were the most effective for change in HbA1c. GLP-1RA and sodium- glucose cotransporter-2 inhibitors led to weight reduction. Apart from the increased risk of hypoglycemia with sulfonylureas, no significant differences in adverse events were observed across regimens.
Conclusion
Early combination therapy effectively improved glycemic control in patients with early T2DM without significantly increasing adverse risks. Future studies should explore new combinations, including potent GLP-1RA.

Technology/Device
Current Status of Continuous Glucose Monitoring Use in South Korean Type 1 Diabetes Mellitus Population–Pronounced Age-Related Disparities: Nationwide Cohort Study: Ji Yoon Kim, Seohyun Kim, Jae Hyeon Kim; Received December 9, 2024 Accepted February 3, 2025 Published online April 28, 2025; DOI: https://doi.org/10.4093/dmj.2024.0804 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
This study aims to identify the status of continuous glucose monitoring (CGM) use among individuals with type 1 diabetes mellitus (T1DM) in South Korea and to investigate whether age-related disparities exist.
Methods
Individuals with T1DM receiving intensive insulin therapy were identified from the Korean National Health Insurance Cohort (2019–2022). Characteristics of CGM users and non-users were compared, and the prescription rates of CGM and sensor- augmented pump (SAP) or automated insulin delivery (AID) systems according to age groups (<19, 19–39, 40–59, and ≥60 years) were analyzed using chi-square tests. Glycosylated hemoglobin (HbA1c) levels and coefficients of variation (CV) among CGM users were also examined.
Results
Among the 56,908 individuals with T1DM, 10,822 (19.0%) used CGM at least once, and 6,073 (10.7%) used CGM continuously. Only 241 (0.4%) individuals utilized either SAP or AID systems. CGM users were younger than non-users. The continuous prescription rate of CGM was highest among individuals aged <19 years (37.0%), followed by those aged 19–39 years (15.8%), 40–59 years (10.7%), and ≥60 years (3.9%) (P<0.001 for between-group differences). Among CGM users, HbA1c levels decreased from 8.7%±2.4% at baseline to 7.2%±1.2% at 24 months, and CV decreased from 36.6%±11.9% at 3 months to 34.1%±12.7% at 24 months.
Conclusion
Despite national reimbursement for CGM devices, the prescription rates of CGM remain low, particularly among older adults. Given the improvements in HbA1c and CV following CGM initiation, more efforts are needed to increase CGM utilization and reduce age-related disparities.

Lifestyle and Behavioral Interventions
The Preventive Effect of Physical Activity on Gestational Diabetes Mellitus: A Korean Longitudinal Prospective Cohort Study: Ji Hyae Lim, Min Hyoung Kim, Hye-Ji Han, Su Ji Yang, Myung-Gwan Kim, Hyun Jung Lee, You Jung Han, Jin Hoon Chung, Dong Wook Kwak, Seongwoo Yang, Moon Young Kim, Hyun Mee Ryu; Received May 30, 2024 Accepted December 3, 2024 Published online April 23, 2025; DOI: https://doi.org/10.4093/dmj.2024.0280 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
To assess longitudinally physical activity patterns and intensity from pre-pregnancy to postpartum and evaluate the association between timing and type of physical activity and the development of gestational diabetes mellitus (GDM).
Methods
The Korean Pregnancy Outcome Study (KPOS) is a prospective cohort study conducted from 2013 to 2017. Our study included 3,457 participants with singleton pregnancies in KPOS, classified according to the pregnancy outcome: GDM (n=231) and normal (n=3,226). Physical activity data were collected at five time points using the short form of the International Physical Activity Questionnaire: before pregnancy, at 12, 24, and 36 gestational weeks (GW), and 6–8 weeks postpartum. Pre-pregnancy physical activity was collected through recall at 12 GW.
Results
Maternal age, pre-pregnancy body mass index, educational status, smoking, mini dietary assessment index, first-degree family history of diabetes, hypertension, parity, pre-existing GDM, and previous macrosomia showed significant differences between the GDM group and the normal group (P<0.05 for all). Pre-pregnancy muscle-strengthening activity was significantly associated with a lower risk of GDM (adjusted odds ratio, 0.46; 95% confidence interval, 0.25 to 0.85).
Conclusion
These findings suggest that physical activity, such as muscle-strengthening activities before pregnancy, could be a preventive strategy to reduce GDM risk. Although the study does not provide evidence that physical activity during pregnancy and postpartum reduces GDM risk, it offers significant insights into the importance of maintaining a healthy level of physical activity from pre-pregnancy to prevent GDM.

Complications
Risk of End-Stage Kidney Disease in Individuals with Diabetes Living Alone: A Large-Scale Population-Based Study: Kyunghun Sung, Jae-Seung Yun, Bongseong Kim, Hun-Sung Kim, Jae-Hyoung Cho, Yong-Moon Mark Park, Kyungdo Han, Seung-Hwan Lee; Received September 20, 2024 Accepted December 12, 2024 Published online April 5, 2025; DOI: https://doi.org/10.4093/dmj.2024.0578 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Previous research has linked solitary living to various adverse health outcomes, but its association with diabetic complications among individuals with type 2 diabetes mellitus (T2DM) remains underexplored. We examined the risk of endstage kidney disease (ESKD) in individuals with diabetes living alone (IDLA).
Methods
This population-based cohort study used the National Health Information Database of Korea, which included 2,432,613 adults with T2DM. Household status was determined based on the number of registered family members. IDLA was defined as continuously living alone for 5 years or more. A multivariable Cox proportional hazards model was used to evaluate the association between living alone and the risk of developing ESKD.
Results
During a median follow-up of 6.0 years, 26,691 participants developed ESKD, with a higher incidence observed in the IDLA group than in the non-IDLA group. After adjusting for confounding variables, the hazard ratio for ESKD in the IDLA group was 1.10 (95% confidence interval, 1.06 to 1.14). The risk of ESKD was particularly elevated in younger individuals, those without underlying chronic kidney disease, with longer durations of living alone, and with low household income. Adherence to favorable lifestyle behaviors (no smoking, no alcohol consumption, and engaging in regular exercise) was associated with a significantly lower risk of ESKD, with a more pronounced effect in the IDLA group.
Conclusion
Living alone was associated with a higher risk of ESKD in individuals with T2DM. Tailored medical interventions and social support for IDLA are crucial for the prevention of diabetic complications.

Basic and Translational Research
Effect of 4 Weeks Resonance Frequency Breathing on Glucose Metabolism and Autonomic Tone in Healthy Adults: Benedict Herhaus, Andreas Peter, Julia Hummel, Thomas Kubiak, Martin Heni, Katja Petrowski; Received October 19, 2024 Accepted February 3, 2025 Published online April 3, 2025; DOI: https://doi.org/10.4093/dmj.2024.0647 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
The autonomic nervous system plays a crucial role in the brain’s communication with metabolically important peripheral organs, modulating insulin sensitivity and secretion. Increased sympathetic tone is a common feature in prediabetes and diabetes. The parasympathetic nervous system activity might be improvable through resonance frequency breathing (RFB) with heart rate variability biofeedback (HRV-BF) training.
Methods
We here investigated the effect of a 4-week mobile RFB-HRV-BF intervention on glucose metabolism and HRV of 30 healthy adults (17 females; mean age 25.77±3.64 years; mean body mass index 22.65±2.95 kg/m²). Before and after the intervention, glucose metabolism was assessed by 75 g oral glucose tolerance tests (with blood sampling every 30 minutes over 2 hours) and HRV was measured through electrocardiography.
Results
RFB-HRV-BF training did not influence glucose metabolism in healthy adults but reduced fasting as well as 2-hour-postload glucose in participants categorized as more insulin resistant before the intervention. In addition, RFB-HRV-BF training was associated with an increase in the time and frequency domain HRV parameters standard deviation of all NN-intervals, root mean square successive differences, HRV high-frequency and HRV low-frequency after 4 weeks of intervention.
Conclusion
Our findings introduce RFB-HRV-BF training as an effective tool to modulate the autonomic nervous system with a shift towards the parasympathetic tone. Along with the observed decrease in glycemia in those with lower insulin sensitivity, RFB-HRV-BF training emerges as a promising non-pharmacological approach to improve glucose metabolism which has to be further investigated in prediabetes and diabetes.

Complications
The Causal Relationship and Association between Biomarkers, Dietary Intake, and Diabetic Retinopathy: Insights from Mendelian Randomization and Cross-Sectional Study: Xuehao Cui, Dejia Wen, Jishan Xiao, Xiaorong Li; Received November 17, 2024 Accepted December 12, 2024 Published online March 31, 2025; DOI: https://doi.org/10.4093/dmj.2024.0731 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Diabetic retinopathy (DR) is a major cause of vision loss, linked to hyperglycemia, oxidative stress, and inflammation. Despite advancements in DR treatments, approximately 40% of patients do not respond effectively, underscoring the need for novel, noninvasive biomarkers to predict DR risk and progression. This study investigates causal relationships between specific biomarkers, dietary factors, and DR development using Mendelian randomization (MR) and cross-sectional data.
Methods
We conducted a two-phase analysis combining MR and cross-sectional methods. First, MR analysis examined causal associations between 35 biomarkers, 226 dietary factors, and DR progression using data from the UK Biobank and Genome-Wide Association Study (GWAS) datasets. Second, a cross-sectional study with National Health and Nutrition Examination Survey (NHANES) and a clinical cohort from Tianjin Medical University Eye Hospital validated findings and explored biomarkers’ predictive capabilities through a nomogram-based prediction model.
Results
MR analysis identified eight biomarkers (e.g., glycosylated hemoglobin [HbA1c], high-density lipoprotein cholesterol [HDL-C]) with significant causal links to DR. Inflammatory markers and metabolic factors, such as high glucose and HDL-C levels, were strongly associated with DR risk and progression. Specific dietary factors, like cheese intake, exhibited protective roles, while alcohol intake increased DR risk. Validation within NHANES and Tianjin cohorts supported these causal associations.
Conclusion
This study elucidates causal relationships between biomarkers, dietary habits, and DR progression, emphasizing the potential for personalized dietary interventions to prevent or manage DR. Findings support the use of HDL-C, HbA1c, and dietary factors as biomarkers or therapeutics in DR, though further studies are needed for broader applicability.

Basic and Translational Research
Inflammatory Milieu by Crosstalk between Glomerulus and Proximal Tubular Cells in Type 2 Diabetes Mellitus Kidney Disease: Peong Gang Park, Juhyeon Hwang, Yongjun Kim, Minki Hong, Donghwan Yun, Haein Yoon, Chaelin Kang, Sohyun Bae, Soo Heon Kwak, Yong Chul Kim, Kyung Chul Moon, Dong-Sup Lee, Yon Su Kim, Hee Gyung Kang, Hyun Je Kim, Seung Seok Han; Received September 4, 2024 Accepted December 12, 2024 Published online March 31, 2025; DOI: https://doi.org/10.4093/dmj.2024.0535 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Due to the limited availability of therapeutic agents for type 2 diabetic kidney disease (T2DKD), there is a need for further knowledge derived from experimental models and innovative techniques. In addressing this issue, single-cell RNA sequencing (scRNA-seq) has been exclusively applied to a genetically modified diabetic kidney disease model, but not to an induced model representing T2DKD. Herein, we analyzed scRNA-seq and other experiments from an induced T2DKD model and validated the results in human-derived biospecimens.
Methods
The model was induced by combining a high-fat diet with streptozotocin to simulate induced T2DKD. scRNA-seq, histological, and flow cytometric analyses were conducted, and the results were compared with control mice. The findings were then applied to human T2DKD kidneys.
Results
Biochemical and histological analyses unveiled early-stage T2DKD features, such as hyperfiltration, increased proteinuria, glomerulomegaly, and interstitial fibrosis. scRNA-seq identified that proximal tubules secreted a variety of chemokines, potentially in response to crosstalk with glomeruli. Notably, C-X-C motif chemokine 12 (CXCL12) emerged as a key player in potentially promoting T-cell recruitment. Flow cytometry substantiated T-cell infiltration into the kidney of the T2DKD model. This finding was further corroborated in human biopsied kidney tissues, showing a correlation between elevated CXCL12 levels and T2DKD progression.
Conclusion
The induced T2DKD model highlights the pivotal role of CXCL12-mediated T-cell infiltration, stemming from the crosstalk between proximal tubules and glomeruli. This data serves as a foundation for future studies, promising a therapeutic target for T2DKD.

Metabolic Risk/Epidemiology
Early Enrollment in Diabetes Pay-for-Performance Program Reduced Loss of Life Expectancy in Newly-Diagnosed Patients with Type 2 Diabetes Mellitus: Yu-Ching Chen, Wei-Ming Wang, Boniface J. Lin, Jung-Der Wang, Li-Jung Elizabeth Ku; Received August 25, 2024 Accepted December 3, 2024 Published online March 26, 2025; DOI: https://doi.org/10.4093/dmj.2024.0507 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Diabetes is associated with reduced lifespan. To explore pay-for-performance (P4P) program and life expectancy (LE), we investigated the impact of interval between diabetes diagnosis and enrollment in P4P program on loss-of-LE among patients with diabetes in Taiwan.
Methods
From diabetes mellitus health database, which collected all newly-diagnosed patients with diabetes by calendar year, we selected patients, aged 40 to 64, with 503,662 in P4P group and 450,071 in non-P4P group, respectively, from 2004 to 2015, and followed them until the end of 2018 using Kaplan–Meier survival analysis. We simulated age-, gender-, and calendar yearmatched referents for each group through Monte Carlo method from Taiwan’s vital statistics. We constructed a restricted cubic spline model on logit-transformed relative survival between each group and its corresponding matched referents, and applied a rolling-over algorithm month-by-month to extrapolate the survival function of each index group to lifetime to estimate the LE, which was subtracted from that of matched referents to obtain the loss-of-LE.
Results
We found stratified analysis by interval showed that the earlier the enrollment, the lower the loss-of-LE, namely, 0.06±0.72 years for interval <1 year, 0.05±0.59 years for interval 1–4 years, 10.01±0.11 years for interval 5–9 years, and 12.77±0.14 years for interval 10–15 years, respectively (P<0.001), compared with 2.60±0.14 years for non-P4P group.
Conclusion
Early enrollment in the P4P program was associated with reduced loss-of-LE, indicating P4P might gain life if implemented early after diabetes diagnosis.

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