Diabetes & Metabolism Journal

Original Articles

Metabolic Risk/Epidemiology
Birth Weight, Adult Fat Distribution, and Type 2 Diabetes Mellitus Risk: Sex-Specific Study in a Large Prospective Cohort: Ding Ding, Xiaoyi Luo, Shuhao Chen, Zhilin Liu, Xiaojing Kuang, Tianrui Zhuang, Gaoli She, Hailan Huang, Xingfen Yang, Jie Li, Ran An; Received June 29, 2025 Accepted October 23, 2025 Published online January 29, 2026; DOI: https://doi.org/10.4093/dmj.2025.0569 [Epub ahead of print]

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Regional fat distribution is a key determinant of metabolic risk, independent of total adiposity. However, the developmental origins of fat depot-specific accumulation and its contribution to type 2 diabetes mellitus (T2DM) remain unclear. We aimed to investigate whether adult fat distribution mediates the association between birth weight (BW) and T2DM risk.
Methods
We analyzed 30,718 diabetes-free UK Biobank participants with magnetic resonance imaging/dual-energy X-ray absorptiometry derived measures of visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue, and gynoid adipose tissue (GAT), liver fat fraction (LFF), pancreatic fat fraction (PFF), and muscle fat infiltration (MFI). Fat depots were adjusted for body mass index (BMI) using sex-specific residuals. Cox regression assessed associations of BW and fat depots with T2DM risk. Mediation analysis assessed indirect effects of fat distribution.
Results
Lower BW was associated with a higher risk of T2DM (hazard ratio per 1 kg increase, 0.71; 95% confidence interval, 0.64 to 0.79), with stronger effects in women. Lower BW was linked to greater VAT, LFF, and PFF, and lower GAT, independent of BMI. Higher levels of VAT, LFF, and PFF were associated with increased T2DM risk, while GAT was protective. Mediation analysis revealed that fat distribution partially mediated the BW-T2DM relationship, with LFF showing the strongest mediation effect (11%). Mediation patterns differed by sex: LFF and VAT were the predominant mediators in women, while LFF and GAT contributed substantially in men.
Conclusion
Fat distribution—particularly liver and visceral fat—partially mediates the BW-T2DM relationship, independent of BMI. These findings highlight the clinical importance of fat depot profiling in understanding the developmental origins of diabetes and guiding early risk stratification.

Complications
Optimizing Early Detection of Diabetic Kidney Disease through Synergistic Biomarkers and Serum Metabolites in Human: Xianke Zhou, Yuan Gui, Jia-Jun Liu, Shijia Liu, Dongning Liang, Yuanyuan Wang, Henry Wells Shaffer, Samantha Mae Mallari, Cameron Jones, Priya Gupta, Dier Li, Ke Zhang, Ying Yu, Jianling Tao, Yanlin Wang, Silvia Liu, Dong Zhou, Haiyan Fu; Received March 8, 2025 Accepted September 16, 2025 Published online January 29, 2026; DOI: https://doi.org/10.4093/dmj.2025.0193 [Epub ahead of print]

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Diabetic kidney disease (DKD) progresses to end-stage renal disease more rapidly than chronic kidney disease due to persistent hyperglycemia and early activation of multiple pathways. Early detection of DKD is crucial to identify subtle kidney damage before clinical symptoms appear.
Methods
This study combined human serum proteomics and public single-cell RNA sequencing and spatial transcriptomics data from diabetic kidneys to identify key biomarkers for DKD diagnosis. These biomarkers were validated in multiple organs of db/db mice at early and advanced stages. In a discovery cohort, sera from 173 healthy adults and 444 type 2 diabetes mellitus (T2DM) patients, with or without kidney disease, were analyzed using metabolomics and enzyme-linked immunosorbent assay (ELISA). Multiple machine learning algorithms were developed to integrate synergistic biomarkers and serum metabolites for DKD early detection, with results validated in 435 participants from four independent clinical cohorts.
Results
Metalloproteinase-7 (MMP-7) and tenascin C (TNC) were elevated in human diabetic kidneys at the single-cell and spatial levels. Proteomics indicated upregulation of serum amyloid A1 (SAA1) and TNC in DKD patients’ serum. In db/db mice, all three biomarkers increased in multiple organs by 18 weeks of age. In DKD patient sera, MMP-7 and TNC levels were consistently elevated across cohorts. The new algorithms combining MMP-7, SAA1, and TNC enhanced early-stage DKD detection, with about 13% improvements in accuracy when serum metabolites were included to distinguish the progression from early to advanced stages after DKD.
Conclusion
Integrating synergistic biomarkers with serum metabolomics enhances early detection of DKD, potentially improving outcomes by slowing disease progression in T2DM patients.

Guideline/Statement/Fact Sheet
Health Effects of Sugar-Sweetened and Artificially Sweetened Beverages: Umbrella Review and Evidence-Based Consensus Statement of the Korean Diabetes Association and the Korean Nutrition Society: Jong Han Choi, SuJin Song, Soo Kyoung Kim, Jae Won Cho, Jae Hyun Bae, Shinje Moon, Jeong Hyun Lim, YeonHee Lee, Ji-Yun Hwang, YoonJu Song, Sang Soo Kim; Diabetes Metab J. 2026;50(1):32-46. Published online January 1, 2026; DOI: https://doi.org/10.4093/dmj.2025.0848

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Background
Excess intake of added sugars contributes to obesity, type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and premature mortality. Sugar-sweetened beverages (SSBs), the main source of added sugars, are consistently linked to adverse outcomes. Artificially sweetened beverages (ASBs) have been suggested as short-term substitutes, but evidence regarding benefits and harms remains inconclusive, and guidance is lacking.
Methods
This consensus statement draws on a structured evidence review combining two approaches: an updated meta-analysis of randomized controlled trials (RCTs) assessing short- to intermediate-term effects of replacing SSBs with ASBs on weight and metabolic outcomes; and an umbrella review of systematic reviews of cohort studies evaluating long-term associations of SSBs and ASBs with major outcomes, including mortality, CVD, and T2DM.
Results
In 14 RCTs (3–76 weeks), replacing SSBs with ASBs produced modest reductions in body weight (–0.73 kg) and body fat (–0.72%), with inconsistent effects on glycemic and cardiometabolic markers. Evidence from 20 systematic reviews of cohorts (up to 34 years follow-up) showed that higher intake of both SSBs and ASBs was associated with increased risks of T2DM, CVD, and mortality, with relative risks for ASBs similar to those for SSBs.
Conclusion
ASBs may serve as a short-term substitution for individuals with high SSB intake, particularly those at elevated metabolic risk. However, regular or long-term use is not recommended due to uncertain safety and potential reinforcement of sweet preference. Public health strategies should emphasize reducing both SSBs and ASBs, prioritizing water and unsweetened beverages as the ultimate goal.

Citations

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Do Not Replace Your Sugar, Simply Eat Less!
Jeehyun Lee, Sunghwan Suh
Diabetes & Metabolism Journal.2026; 50(1): 30. CrossRef

Others
Efficacy and Safety of HD-6277, a Novel G Protein-Coupled Receptor 40 Agonist, in Individuals with Type 2 Diabetes Mellitus: A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 2 Clinical Trial: Yong-ho Lee, Kyung Wan Min, Jun Hwa Hong, Soo Lim, Jae Myung Yu, Choon Hee Chung, Jun Sung Moon, Jong Chul Won, Chul Woo Ahn, Jie-Eun Lee, Tae Nyun Kim, Byung-Wan Lee; Received July 17, 2025 Accepted October 11, 2025 Published online December 19, 2025; DOI: https://doi.org/10.4093/dmj.2025.0528 [Epub ahead of print]

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This study assessed the efficacy and safety of HD-6277, a novel oral G protein-coupled receptor 40 (GPR40) agonist in adults with inadequate control of type 2 diabetes mellitus (T2DM).
Methods
This double-blind, randomized, placebo-controlled phase 2 trial recruited 112 individuals aged 18–75 years with T2DM and glycosylated hemoglobin (HbA1c) levels between 7.0% and 10.0% while on diet and exercise alone for at least 8 weeks before screening. Parallel-group randomized trials of HD-6277 (50 and 100 mg groups vs. placebo) were conducted for 12 weeks. The primary outcome was the change in HbA1c levels from baseline to week 12. Secondary outcomes included changes in HbA1c, fasting plasma glucose (FPG), postprandial glucose, insulin, glycoalbumin, and C-peptide at weeks 4, 8, and 12.
Results
At week 12, HD-6277 at 50 and 100 mg demonstrated statistically significant reductions in HbA1c compared to placebo, with least square (LS) mean differences of –0.73% (95% confidence interval [CI], –1.11 to –0.35; P=0.0002) and –0.85% (95% CI, –1.21 to –0.50; P<0.0001), respectively. Both doses also produced clinically meaningful reductions in FPG. Additionally, HD- 6277 at 100 mg significantly increased the insulinogenic index compared to placebo, with an LS mean difference of 1.91 (95% CI, 0.34 to 3.48; P=0.0175). No clinically relevant treatment-related adverse events were observed.
Conclusion
HD-6277 at 50 and 100 mg improved glycemic control and was well-tolerated in adults with T2DM inadequately managed with diet and exercise. GPR40 agonists may offer a promising new therapeutic option for T2DM.

Pharmacotherapy
Efficacy and Safety of Enavogliflozin as Add-on in Adults with Type 2 Diabetes Mellitus Inadequately Controlled with Insulin or Insulin with Other Antidiabetic Drugs: Jun Hwa Hong, Kyung Wan Min, Chang Beom Lee, Parinya Chamnan, Thanitha Sirirak, Kiran Sony, Sarinya Sattanon, Hae Jin Kim, Sang-Yong Kim, Younghee Kim, Jung A Heo, Jae Min Cho, Jae Jin Nah, Mi Hee Park, Jae Hyeon Kim; Received May 30, 2025 Accepted October 14, 2025 Published online December 15, 2025; DOI: https://doi.org/10.4093/dmj.2025.0477 [Epub ahead of print]

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The study evaluated the efficacy and safety of enavogliflozin, a novel, promising selective sodium-glucose cotransporter 2 inhibitor, as an add-on in adults with type 2 diabetes mellitus (T2DM) inadequately controlled with insulin alone or combined with other antidiabetic drugs (OADs).
Methods
The double-blind, placebo-controlled, multicenter trial was conducted in South Korea and Thailand. Individuals with glycosylated hemoglobin (HbA1c) ≥7.5% after ≥8-week treatment with background insulin alone or combined with ≤2 OADs were randomized to receive enavogliflozin 0.3 mg or placebo (n=116 each) for 24 weeks. The primary outcome was a change in HbA1c at week 24. Secondary outcomes included, among others, changes in body weight, blood pressure, and other measures of glycemic control. Adverse events (AEs) were investigated throughout the study (Clinical trial registration number: NCT05466643).
Results
At week 24, the placebo-adjusted mean change in HbA1c from baseline in the enavogliflozin group was –0.9% (P<0.001). Also, placebo-adjusted mean changes in fasting plasma glucose (–32.4 mg/dL, P<0.001), body weight (–1.3 kg, P<0.001), and total daily dose of insulin (–1.3 units, P=0.010) at week 24 were statistically significant. In addition, a significant decrease in blood pressure and fasting C-peptide was observed in the enavogliflozin group, along with a significant increase in homeostasis model assessment of β-cell function, yet without a concomitant change in homeostasis model assessment of insulinresistance. No significant increase in treatment-related AEs was observed for enavogliflozin.
Conclusion
Enavogliflozin 0.3 mg/day is an efficacious and safe add-on treatment option in T2DM patients controlled inadequately with insulin alone or combined with OADs.

Genetics
Evaluation of Sex-Stratified Polygenic Risk Scores for Type 2 Diabetes Mellitus and Glycemic Traits in the Framingham Heart Study: Ningyuan Wang, Yixin Zhang, Philip Schroeder, Alicia Huerta-Chagoya, Ravi Mandla, James B. Meigs, Alisa K. Manning, Ching-Ti Liu, Josée Dupuis, Josep M. Mercader; Received June 25, 2025 Accepted October 14, 2025 Published online December 9, 2025; DOI: https://doi.org/10.4093/dmj.2025.0557 [Epub ahead of print]

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Diabetes is a multifactorial disease with significant genetic predisposition. Polygenic risk scores (PRS) have been developed to estimate an individual’s genetic risk of a disease. Traditionally, PRS utilize sex-combined genome-wide association studies (GWAS) due to the limited availability of sex-stratified summary statistics. This study explores sex-dimorphic genetic effects and evaluates the potential benefits of incorporating sex-stratified effects in PRS for type 2 diabetes mellitus (T2DM) and glycemic traits by comparing PRS performance derived from sex-combined versus sex-stratified GWAS.
Methods
We performed a sex-heterogeneity test across sex-specific GWAS and identified nine signals with sex-dimorphic effects for T2DM. PRS[sex-combined] and PRS[sex-stratified] were developed using sex-combined and sex-stratified GWAS results for T2DM (41,444 cases and 354,539 controls), fasting glucose (n=120,595) and fasting insulin (n=98,210). We evaluated these PRS models in 8,379 participants (1,303 cases and 7,076 controls) from the Framingham Heart Study not included in the PRS derivation.
Results
Our findings suggest that sex-combined PRS currently offer better predictive performance for T2DM and glycemic traits.
Conclusion
These results highlight the need for larger sex-stratified studies and the optimization of sex-stratified risk models for clinical practice.

Lifestyle and Behavioral Interventions
Risk Determinants of Type 2 Diabetes Mellitus with Severe Obesity and Prediction Model for Diabetes Remission after Bariatric Metabolic Surgery: Zilong Wu, Yuxia Li, Dehui Wang, Bing Wu, Kaisheng Yuan, Yun Liu, Hao Zhu, Sijie Chen, Wah Yang, Ruixiang Hu, Cunchuan Wang; Received April 15, 2025 Accepted September 8, 2025 Published online November 25, 2025; DOI: https://doi.org/10.4093/dmj.2025.0337 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Bariatric metabolic surgery (BMS) has been established as an effective intervention for obesity and type 2 diabetes mellitus (T2DM). However, systematic research addressing the onset of diabetes and post-surgical remission in severely obese populations remains scarce. This study aims to identify risk factors for T2DM in populations with severe obesity undergoing BMS and develop and validate a prediction model for the primary outcome of diabetes remission (DR) 1 year after BMS. This research provides a precise tool for managing T2DM in populations with severe obesity.
Methods
This research utilizes the China Obesity and Metabolic Surgery Database, retrospectively analyzing 3,670 severely obese populations who underwent BMS between January 2014 and January 2024. Differential analysis identified risk factors for T2DM onset, while univariate and multivariate regression analyses identified independent risk factors for DR post-surgery. A prediction model for DR was developed and internally validated.
Results
Factors associated with T2DM onset in severely obese populations included family history of diabetes, hypertension, hyperlipidemia, glycosylated hemoglobin (HbA1c) levels, and fasting plasma glucose. Independent factors influencing DR postsurgery included diabetes duration, surgical method, HbA1c, and insulin requirement. Subsequent model validation confirmed stable performance metrics (area under the curve values training, 0.71; validation, 0.72).
Conclusion
This study identifies risk factors for T2DM onset and a prediction model for DR following BMS in the Chinese severely obese population. It provides a more precise risk assessment tool for patients with severe obesity and T2DM, and lays the groundwork for future multicenter studies and international collaborations.

Pharmacotherapy
Glycemic Improvement with Low-Dose Dulaglutide Is Associated with Leptin and Obestatin Modulation in Type 2 Diabetes Mellitus: Inha Jung, Hangseok Choi, In Young Choi, Hyun Joo Cho, So Young Park, Da Young Lee, Ji A Seo, Nan Hee Kim, Ji Hee Yu; Received July 28, 2025 Accepted September 23, 2025 Published online November 24, 2025; DOI: https://doi.org/10.4093/dmj.2025.0681 [Epub ahead of print]

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Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve glycemic control through insulinotropic and anorectic effects. However, the role of adipokines and appetite-related hormones in mediating the glycemic response remains unclear. This study evaluated changes in abdominal fat, food cravings, and circulating adipokines and gut hormones following dulaglutide treatment and identified predictors of glycemic improvement in type 2 diabetes mellitus (T2DM).
Methods
In this 24-week prospective observational study, 82 patients with T2DM and glycosylated hemoglobin (HbA1c) levels ≥7.0% despite standard therapy received dulaglutide 0.75 mg once weekly. Abdominal computed tomography, the General Food Cravings Questionnaire-Trait, and fasting levels of leptin, adiponectin, obestatin, ghrelin, and resistin were assessed at baseline and week 24. Glycemic responders were defined as those with an HbA1c reduction ≥0.5% and/or HbA1c <7.0% at 24 weeks. Multivariable regression analysis was performed to identify the factors associated with glycemic improvement.
Results
Among the 67 patients who completed the study, dulaglutide significantly reduced HbA1c, food cravings, leptin, and adiponectin levels. Obestatin levels increased modestly. Responders showed greater improvement in β-cell function and more pronounced reductions in food cravings. In the adjusted models, a decrease in leptin and an increase in obestatin were independently associated with HbA1c reduction, while decreased adiponectin was associated with poorer glycemic outcomes. Changes in body mass index or abdominal fat were not associated with glycemic improvement.
Conclusion
Dulaglutide improved glycemic control through mechanisms beyond weight reduction. Hormonal changes in leptin, adiponectin, and obestatin may help predict responses to GLP-1 RAs therapy.

Basic and Translational Research
Targeting PGC-1α by miRNA-374 Simultaneously Improve β-Cell Dysfunction and Suppress Hepatic Glucose Overproduction: Ji-Won Kim, Joonyub Lee, Young-Hye You, Chan-Hee Oh, Heon-Seok Park, Eun Young Lee, Seung-Hwan Lee, Seung-Hyun Ko, Ji-Ho Park, Kun-Ho Yoon; Received April 5, 2025 Accepted August 24, 2025 Published online November 3, 2025; DOI: https://doi.org/10.4093/dmj.2025.0287 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
In this study, we aimed to validate the potential of miR-374 in ameliorating hyperglycemia by regulating peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α) expression in pancreatic islets and liver.
Methods
To identify miRNAs targeting PGC-1α, we performed miRNA chip analysis in rat islets under hyperglycemic and euglycemic conditions. Luciferase reporter assay was performed to identify miR binding sites in the 3’-untranslated region (3’ UTR) of PGC-1α. In db/db mice, miRNA-encapsulated adenoviruses were administered and intraperitoneal glucose tolerance test and glucose stimulated insulin secretion tests were performed. For enhanced delivery to β-cells, we developed exendin-4 (Ex-4) coated cationic lipoparticles (CCLs) encapsulating miRNAs. The therapeutic potential of Ex-4-CCL-miRNA was further evaluated in insulin-producing cells derived from induced pluripotent stem cells.
Results
By analyzing miRNA expression in primary rat islets exposed under hyperglycemic environment, we identified miR-374 as a potential target. In vitro experiments confirmed that miR-374 significantly suppressed PGC-1α expression in β-cells and hepatocytes by binding to its 3’-UTR. In vivo experiments using adenovirus-mediated miR-374 (Ad-miR-374) delivering directly to the pancreas and liver of db/db mice demonstrated improved glycemic control, enhanced insulin secretion, and downregulated hepatic gluconeogenesis-related genes (G6Pase, Pepck, PC). To enhance the clinical applicability of miR-374, we developed Ex-4-CCLs. Ex-4-CCL-miR-374 successfully alleviated hyperglycemia, restored pancreatic islet function, and decreased gluconeogenesis gene expression in db/db mice. Furthermore, Ex-4-CCL-miR-374 improved insulin secretory function in glucotoxicity-exposed human induced pluripotent stem cell-derived insulin producing cells.
Conclusion
Based on these findings, we propose that Ex-4-CCL-miR-374 as a promising therapeutic approach to reverse β-cell dysfunction and improve hepatic insulin resistance in type 2 diabetes mellitus.

Complications
4-Octyl Itaconate Promotes Diabetic Wound Healing by Enhancing Pro-Resolving Macrophages via the Efferocytosis-MCT1-Lactate-GPR132 Pathway and Macrophage-Independent Synergistic Effects: Mengqin Tu, Xiaoli Zou, Xiaozhen Tan, Yijun Liu, Xinxu Ge, Yu Hu, Qiuyue Peng, Linlin Huang, Yan Zeng, Chunxia Jia, Man Guo, Jiao Chen, Yang Long, Yong Xu; Received September 21, 2024 Accepted July 2, 2025 Published online November 3, 2025; DOI: https://doi.org/10.4093/dmj.2024.0579 [Epub ahead of print]

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Background
Diabetic foot ulcers are a severe diabetic complication causing poor healing. Itaconate, a tricarboxylicacid cycle byproduct, has been shown to improve wound healing. This study investigated the potential of 4-octyl itaconate (4-OI), an esterified derivative of itaconate, to modulate efferocytosis andmacrophage pro-resolving function to promote diabetic wound healing.
Methods
A diabetic mouse wound model was used. For in vitro analysis, RAW264.7 macrophages and apoptotic Jurkat cells were cocultured under high glucose (HG, 30 mM). To further evaluate the roles of macrophages, monocarboxylate transporter 1 (MCT1), and lactate in 4-OI-promoted diabetic wound healing, we used clodronate-liposomes (CLD-Lipo) to deplete macrophages, AZD3965 (an MCT1 inhibitors), telmisartan to validate our hypothesis.
Results
In diabetic mice, impaired apoptotic neutrophils clearance and persistent M1 activation delayed wound healing. 4-OI improved diabetic wound repair by enhancing efferocytosis, shifting macrophages toward M2 pro-resolving phenotype, and boosting angiogenesis. 4-OI showed a protective effect mediated by macrophages, while endothelial cells and neutrophils also played synergistic roles in diabetic wound healing. Moreover, 4-OI upregulated MCT1 which, in turn, increased release of lactate triggered by efferocytosis at the wound site. Lastly, we confirmed that pro-resolving effects of 4-OI onmacrophage function were mediated by promoting pro-resolving macrophage proliferation and polarization via efferocytosis-induced lactate release and subsequent activation of G protein-coupled receptor 132 (GPR132).
Conclusion
4-OI promotes diabetic wound healing through macrophage-dependent/independent mechanisms. Moreover, the protective effect of 4-OI on macrophage was mediated through MCT1-mediated lactate release triggered by efferocytosis and subsequent GRP132 activation.

Citations

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Roles of efferocytosis in wound repair: Process, cells, and signals
Yilin Sun, Haiying Guo, Yang Bai, Jin Chen, Yuhong Li
Genes & Diseases.2026; 13(3): 101937. CrossRef

Reviews

Guideline/Statement/Fact Sheet
Bridging Evidence and Practice: A Consensus Statement from the Korean Diabetes Association on Diabetes Screening, Pharmacological Treatment and Severe Diabetes: Jong Han Choi, Shinae Kang, Soo-Kyung Kim, Won Jun Kim, Ji Min Kim, Jaehyun Bae, Jae-Seung Yun, Eonju Jeon, Young-Eun Kim, Jae Hyun Bae, Hun Jee Choe, Young Min Cho, Seung-Hyun Ko, Sang Yong Kim, Hae Jin Kim, You-Cheol Hwang, Min Kyong Moon, Suk Chon, Seon Mee Kang, Hyuk-Sang Kwon, Mi Kyung Kim, You-Bin Lee, Se Hee Min, Jung Hwan Park, Woo Je Lee, Bong-Soo Cha, Byung-Wan Lee; Diabetes Metab J. 2025;49(6):1155-1177. Published online November 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0978

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Abstract PDF Supplementary Material PubReader ePub: This Korean Diabetes Association (KDA) consensus statement bridges global evidence with the Korean clinical context, where large randomized and real-world data remain limited. Recommendations required ≥80% agreement by the committee of clinical practice guideline and approval by the board of directors. The statement comprises three domains: diabetes screening aligned with Korean epidemiology; pharmacologic management guided by pathophysiology and comorbidities; and a severity construct of “severe diabetes mellitus” that links complication-based staging with metabolic grading to match therapeutic intensity to disease complexity. Compared with prior KDA guidelines, this statement introduces substantive advances in three areas. First, screening recommendations are streamlined to emphasize risk-aligned, practical implementation rather than prescriptive test sequences. Second, pharmacologic management applies an individualized framework for drug selection that jointly considers pathophysiology and comorbidities. It operationalizes individualized selection by dominant pathophysiology (insulin resistance vs. insulin insufficiency) and coexisting conditions, and formalizes treatment dynamics—early combination, timely initiation of injectables, avoidance of overbasalization, and structured deintensification. It also prioritizes agents with proven cardiovascular and renal protection and elevates management of obesity and metabolic dysfunction-associated steatotic liver disease as central goals; clinically, insulin should be initiated promptly in hypercatabolic states or suspected islet failure, and technology-enabled care—including continuous glucose monitoring and automated insulin delivery—are integral across all stages. Third, the newly introduced severity construct underpins treatment-intensity decisions across domains without reiterating prescriptive algorithms. Collectively, these recommendations provide a coherent, context-appropriate framework for diabetes screening and management in Korea and identify priorities for future evidence generation.

Lifestyle and Behavioral Interventions
Optimizing Physical Activity Strategies for Older Adults with Diabetes: Hyeon-Jin Yu, Doyoun Hong, Kyuho Kim, Ji Hye Heo, Dong-Hyeok Cho, Yoshitaka Hashimoto, Jae-Seung Yun; Diabetes Metab J. 2025;49(6):1178-1197. Published online November 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0967

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Abstract PDF PubReader ePub: The increasing prevalence of diabetes among older adults has emerged as a major socioeconomic burden. This population is highly heterogeneous, ranging from functionally independent to severely impaired individuals, making it difficult to establish standardized recommendations. Physical activity (PA) is a cornerstone of diabetes management; however, current exercise guidelines do not adequately address the wide spectrum of functional capacities observed in older adults. For those with physical limitations, relatively simple activities such as walking, breaking up sedentary time, incorporating movement into daily routines, and aquatic exercise have been proposed, yet supporting evidence remains limited. This review summarizes the pathophysiologic mechanisms of metabolic and functional changes associated with aging and diabetes—including sarcopenia, altered body composition, and cardiovascular decline—and comprehensively discusses the benefits and precautions of various exercise modalities, tailored recommendations according to diabetes-related complications, and key clinical considerations. We further classified older adults with diabetes into three functional levels, individuals in good health, those with some comorbidities or mild disabilities, and those with high comorbidities and/or functional impairment, and proposed corresponding physical activity strategies for each level. Finally, we highlight practical and feasible approaches, including walking, interrupting sedentary behavior, daily functional movements, and aquatic exercise, to enhance clinical applicability for individuals with reduced physical capacity. These tailored, function-based strategies may help older adults with diabetes achieve safer, more effective, and sustainable improvements in glycemic control and overall health.

Guideline/Statement/Fact Sheet
Defining Severe Diabetes Mellitus: A Consensus Framework for Grading and Staging Diabetes Based on Pathophysiology and Complications: Jae Hyun Bae, Hun Jee Choe, Ye Seul Yang, Mi Hae Seo, Jong Han Choi, Gyuri Kim, Young Sang Lyu, Jeung Hun Han, Shinae Kang, Won Jun Kim, Kyung-Soo Kim, Young Min Cho, Bong Soo Cha, for the Severe Diabetes Mellitus Task Force of the Korean Diabetes Association; Diabetes Metab J. 2025;49(6):1141-1154. Published online October 28, 2025; DOI: https://doi.org/10.4093/dmj.2025.0739

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Diabetes mellitus comprises a heterogeneous group of metabolic disorders differing in etiology, clinical course, and outcomes. Traditional classifications, such as type 1 and type 2 diabetes mellitus, fail to capture the full heterogeneity, including variation in insulin deficiency, insulin resistance, and complication burden. To address these limitations, we propose the Diabetes Grade–Stage Classification, an integrated system that combines pathophysiology-based grading with complication-based staging. Grading quantifies metabolic dysfunction through the assessment of insulin deficiency and insulin resistance. In parallel, staging assesses the extent of target organ damage, particularly in the cardiovascular, renal, ocular, and nervous systems. Together, this framework enables a comprehensive assessment of disease status, identification of vulnerable or high-risk phenotypes, and implementation of risk-adapted management strategies. Clinically, it facilitates personalized care, promotes collaborative coordination, and strengthens physician–patient communication. Furthermore, this framework provides a scalable structure for integrating disease severity into both individual- and population-level interventions. Although the current criteria for grading and staging are based on expert consensus and selected clinical indicators, such as low C-peptide levels and advanced complications, further validation and refinement are needed. In conclusion, the grading and staging system provides an operational tool for classifying the severity of diabetes mellitus and has the potential to extend life expectancy and improve quality of life for people living with diabetes mellitus.

Citations

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Bridging Evidence and Practice: A Consensus Statement from the Korean Diabetes Association on Diabetes Screening, Pharmacological Treatment and Severe Diabetes
Jong Han Choi, Shinae Kang, Soo-Kyung Kim, Won Jun Kim, Ji Min Kim, Jaehyun Bae, Jae-Seung Yun, Eonju Jeon, Young-Eun Kim, Jae Hyun Bae, Hun Jee Choe, Young Min Cho, Seung-Hyun Ko, Sang Yong Kim, Hae Jin Kim, You-Cheol Hwang, Min Kyong Moon, Suk Chon, Seo
Diabetes & Metabolism Journal.2025; 49(6): 1155. CrossRef

Original Articles

Genetics
Elucidating the Epigenetic Landscape of Type 2 Diabetes Mellitus: A Multi-Omics Analysis Revealing Novel CpG Sites and Their Association with Cardiometabolic Traits: Ren-Hua Chung, Chun-Chao Wang, Djeane Debora Onthoni, Ben-Yang Liao, Tzu-Sheng Hsu, Eden R. Martin, Chao A. Hsiung, Wayne Huey-Herng Sheu, Hung-Yi Chiou; Diabetes Metab J. 2026;50(1):153-164. Published online October 28, 2025; DOI: https://doi.org/10.4093/dmj.2025.0041

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Background
Type 2 diabetes mellitus (T2DM) is a complex, multifactorial disease with a significant global burden. Although genome-wide association studies (GWAS) have identified many T2DM-associated variants, most lie in non-coding regions, making it difficult to interpret their functional roles.
Methods
We aimed to identify genetically regulated Cytosine–phosphate–Guanine (CpG) sites associated with T2DM by conducting a methylome-wide association study (MWAS), followed by Mendelian randomization (MR) and functional validation using human pancreatic cells and mouse models. MWAS was performed using summary statistics from large-scale GWAS and a DNA methylation (DNAm) prediction model to test associations between genetically predicted DNAm and T2DM.
Results
We identified 111 CpG sites significantly associated with T2DM in Europeans, including 8 novel sites near genes not previously linked to T2DM. These findings were replicated in independent datasets. Many CpGs also showed associations with cardiometabolic traits, highlighting shared epigenetic mechanisms. Trans-ethnic MR analysis confirmed consistent effects for six CpGs in East Asians. Functional analysis revealed that several CpGs regulate gene expression in human pancreatic α- and β-cells. Among them, 2´-5´-oligoadenylate synthetase like (OASL) expression, regulated by a significant CpG, was differentially expressed in α-cells of T2DM cases compared to controls. Supporting evidence from mouse models suggests a role for OASL in glucose regulation.
Conclusion
Our study identifies novel genetically regulated CpG sites associated with T2DM risk and highlights OASL as a potential epigenetic regulator of glucose metabolism in α-cells. These findings provide mechanistic insights into the epigenetic architecture of T2DM and suggest potential targets for cross-ethnic biomarker development and therapeutic intervention.

Citations

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Unravelling the molecular mechanisms causal to type 2 diabetes across global populations and disease-relevant tissues
Ozvan Bocher, Ana Luiza Arruda, Satoshi Yoshiji, Chi Zhao, Alicia Huerta-Chagoya, Chen-Yang Su, Xianyong Yin, Davis Cammann, Henry J. Taylor, Jingchun Chen, Ken Suzuki, Ravi Mandla, Ta-Yu Yang, Fumihiko Matsuda, Josep M. Mercader, Jason Flannick, James B.
Nature Metabolism.2026;[Epub] CrossRef

Pharmacotherapy
Efficacy and Safety of High-Dose Pioglitazone as Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Dapagliflozin and Metformin: Double-Blind, Randomized, Placebo-Controlled Trial: Jun Hwa Hong, Kyung Ah Han, You-Cheol Hwang, Eun-Gyoung Hong, Hae Jin Kim, Chang Beom Lee, Ho Chan Cho, Jong Chul Won, Hun-Sung Kim, Eui-Hyun Kim, Gwanpyo Koh, Kwang Hyun Ahn, Kyong Soo Park; Received November 14, 2024 Accepted May 29, 2025 Published online October 28, 2025; DOI: https://doi.org/10.4093/dmj.2024.0696 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
This study investigated the efficacy and safety of pioglitazone 30 mg/day add-on to inadequately controlled type 2 diabetes mellitus (T2DM) patients with treatment of dapagliflozin and metformin.
Methods
In this multicenter (34 sites), double-blind, randomized, phase 3 study, patients with T2DM with an inadequately controlled glycosylated hemoglobin (HbA1c) over 7.0% to treatment with dapagliflozin (10 mg/day) and metformin (≥1,000 mg/day) were randomized to receive additional pioglitazone 30 mg/day (n=124) or placebo (n=122) for 24 weeks. The primary outcome was the mean change of HbA1c from baseline to 24 weeks treatment. The efficacy and safety were evaluated with open label extension period, switching placebo to pioglitazone 30 mg/day at 48 weeks (ClinicalTrials.gov identifier: NCT05296044).
Results
The HbA1c after 24 weeks treatment reduced from 7.8%±0.8% to 7.0%±0.6% (P<0.0001). The proportions of patients who achieved HbA1c less than 7.0% at 24 weeks were significantly higher in pioglitazone add-on group (51.61% in pioglitazone vs. 22.95% in placebo, P<0.0001), or less than 6.5% at 24 weeks (21.77% in pioglitazone vs. 2.46% in placebo, P<0.0001). Body weight gain was 2.0 kg at 24 weeks with pioglitazone 30 mg/day and –0.6 kg at 24 weeks with placebo.
Conclusion
Addition of pioglitazone 30 mg/day to T2DM patients who did not reach the target HbA1c (≤7%) with treatment of dapagliflozin 10 mg/day and metformin over 1,000 mg/day showed effective glucose lowering efficacy without significant hypoglycemia and good tolerability with low prevalence of edema in spite of modest weight gain.

Cardiovascular Risk/Epidemiology
Prognostic Impact of Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Coronary Ischemia: A Retrospective Cohort Study: Haochen Xuan, Yik-Ming Hung, Ran Guo, Qingwen Ren, Jiayi Huang, Jingnan Zhang, Wenli Gu, Ho-Leung Chan, Gaozhen Cao, Run Wang, Calvin Ka-Lam Leung, Tongda Xu, Kai-Hang Yiu; Received March 11, 2025 Accepted July 22, 2025 Published online October 24, 2025; DOI: https://doi.org/10.4093/dmj.2025.0200 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Patients with type 2 diabetes mellitus (T2DM) and coronary ischemia face an exceptionally elevated risk, and the achievement of complete revascularization (CR) within this population could be challenging.
Methods
Patients with T2DM and coronary ischemia based on coronary angiography and retrospective angiographic fractional flow reserve analysis between 2014 and 2016 were included. The impact of the extent of revascularization on the improvement of endpoint events by sodium-glucose cotransporter 2 (SGLT2) inhibitors was analyzed. The primary study endpoint was major adverse cardiac events (MACE), while all-cause mortality served as secondary endpoints. Kaplan-Meier analysis and Cox proportional hazards regression model were adopted to assess the association between SGLT2 inhibitors and endpoint incidence.
Results
A total of 671 patients were identified. Among them, 206 (30.7%) were prescribed with SGLT2 inhibitors, while 484 (72.1%) achieved CR after the operation. During a mean 36-month follow-up, 100 MACE and 89 all-cause mortality were recorded. SGLT2 inhibitor users demonstrated lower rates of MACE (8.3% vs. 17.8%, P=0.002) and all-cause mortality (6.3% vs. 16.3%, P<0.001) compared to non-users. After adjusting for confounding factors in multivariable Cox analysis, the association between SGLT2 inhibitors and reduced MACE incidence remained consistent both in the CR and incomplete revascularization subgroups (hazard ratio [HR], 0.498; 95% confidence interval [CI], 0.246 to 0.938; P=0.040; and HR, 0.341; 95% CI, 0.123 to 0.805; P=0.023, respectively).
Conclusion
SGLT2 inhibitors were found to be associated with a reduced risk of 3-year MACE and all-cause mortality in patients with T2DM and coronary ischemia, regardless of extent of revascularization.

Metabolic Risk/Epidemiology
Association of Remnant Cholesterol Inflammation Index with Cardiovascular Risks and All-Cause Mortality in Individuals with Diabetes or Prediabetes: Qi-Lin Ma, Lei-Lei Du, Jia Peng; Received April 8, 2025 Accepted June 27, 2025 Published online October 2, 2025; DOI: https://doi.org/10.4093/dmj.2025.0305 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Remnant cholesterol (RC) and low-grade inflammation are established contributors to cardiovascular disease (CVD) risks in diabetes. However, their combined prognostic impact remains unclear in dysglycemia. We evaluated the remnant cholesterol inflammation index (RCII), integrating RC and high-sensitivity C-reactive protein (hsCRP), for predicting mortality and CVD risks in diabetes/prediabetes.
Methods
This study included 2206 United States adults with diabetes/prediabetes from National Health and Nutrition Examination Survey 2015–2018. RCII was calculated as [RC (mg/dL)×hsCRP (mg/L)]/10. All-cause mortality was tracked via National Death Index until 2019; CVD risk was assessed cross-sectionally. Cox proportional hazard regression determined the hazard ratio (HR) and 95% confidence intervals (CIs) of RCII for all-cause mortality. Logistic regression models estimated the odds ratio (OR) and 95% CIs of RCII for CVD risks.
Results
For CVD risks, Q4 vs. Q1 demonstrated increased odds (OR, 2.32; 95% CI, 1.23 to 4.37), though per-standard deviation (SD) increments were non-significant (OR, 1.15; 95% CI, 0.98 to 1.35; P=0.083). During a median of 38 months follow-up, higher RCII quartiles showed graded associations with all-cause mortality (Q4 vs. Q1: HR, 2.45; 95% CI, 1.08 to 5.58; per 1-SD increase: HR, 1.21; 95% CI, 1.08 to 1.35). Restricted cubic splines confirmed dose-dependent relationships for CVD risks and all-cause mortality (all P=0.005 for overall). Subgroup analyses revealed consistent mortality associations but sex-specific CVD interactions (P=0.047 for interaction).
Conclusion
Our study found the RCII as a biomarker for predicting all-cause mortality and CVD risks in individuals with prediabetes or diabetes, highlighting the synergistic effects of RC and low-grade inflammation on adverse outcomes in this population and may facilitate early identification of individuals at heightened risk for CVD.

Basic and Translational Research
PUM2 Lowers HDAC9 mRNA Stability to Improve Contrast-Induced Acute Kidney Injury through Attenuating Oxidative Stress and Promoting Autophagy: Wei Chen, Hengcheng Lu, Wenni Dai, Hao Li, Yinyin Chen, Guoyong Liu, Liyu He; Received July 18, 2024 Accepted May 21, 2025 Published online September 10, 2025; DOI: https://doi.org/10.4093/dmj.2024.0396 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub

Background
Contrast-induced acute kidney injury (CIAKI) is the third cause of hospital-acquired acute kidney injury and diabetes mellitus (DM) was identified as a risk factor for CIAKI. However, the molecular mechanism underlying DM-CIAKI remains unclear, which needs further investigation.
Methods
DM-CIAKI models of mice and cells were established. The functions of kidneys were evaluated by detecting indicators and using hematoxylin and eosin staining. The abundance of genes and proteins was evaluated by real-time quantitative reverse transcription polymerase chain reaction, immunohistochemistry, immunofluorescence, and Western blot. Glutathione peroxidase, superoxide dismutase, and malondialdehyde were measured using commercial kits and reactive oxygen species was detected using dihydroethidium (DHE) probe and 2ʹ,7ʹ-dichloroflfluorescein diacetate (DCFH-DA) method. Apoptosis of tissues and cells was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Cell viability and proliferation were measured using Cell Counting Kit-8 and 5-ethynyl-2ʹ-deoxyuridine (EdU) assay. The interaction between pumilio RNA binding family member 2 (PUM2) and histone deacetylase 9 (HDAC9) was validated using RNA immunoprecipitation (RIP) and RNA pull-down.
Results
PUM2 expression was observably reduced in DM-CIAKI models while HDAC9 expression was notably boosted. Subsequently, PUM2 silencing resulted in aggravation of kidney injury in DM-CIAKI mice through enhancing oxidative stress and suppressing autophagy, while HDAC9 inhibitor or HDAC9 silencing achieved the opposite results. In terms of mechanism, PUM2 could suppress stability of HDAC9 mRNA to attenuate HDAC9 expression. Furthermore, HDAC9 overexpression abolished PUM2 overexpression-mediated oxidative stress inhibition and autophagy promotion in high glucose and contrast media treatments-induced human kidney-2 (HK-2) cells.
Conclusion
PUM2 overexpression suppressed oxidative stress and promoted autophagy to alleviate renal injury in DM-CIAKI through interacting with HDAC9 mRNA, which mediated degradation of HDAC9 mRNA and inhibition of HDAC9 expression.

Citations

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Purpurin Rescues Contrast-Induced Acute Rat Kidney Injury via Inducing Autophagy and Inhibiting Apoptosis
Kangxu He, Xiaoying Sun, Xinhui Pan, Xiaoda Yang, Qi Wang, Kai Liao
Pharmaceuticals.2026; 19(1): 116. CrossRef
Rubia cordifolia L. Dichloromethane Extract Ameliorates Contrast-Induced Acute Kidney Injury by Activating Autophagy via the LC3B/p62 Axis
Xiaoying Sun, Kangxu He, Guanzhong Chen, Xiaoda Yang, Xinhui Pan, Kai Liao
Molecules.2026; 31(2): 316. CrossRef

Basic and Translational Research
Pancreatic Islet Transplantation in Extrahepatic Sites: Evaluation of the Venous Sac in Large Mammal Models: Giorgi Kenchadze, Ivane Abiatari, Antonello Pileggi, Norma S. Kenyon, Dora M Berman, R. Damaris Molano, Konstantine Gogichaishvili, Revaz Otarashvili, Anzor Tchavtchavadze, Teona Midelashvili, Mariam Motsikulashvili, Camillo Ricordi, Thierry Berney, Ekaterine Berishvili; Received July 19, 2024 Accepted April 28, 2025 Published online September 8, 2025; DOI: https://doi.org/10.4093/dmj.2024.0400 [Epub ahead of print]

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Abstract PDF PubReader ePub: Background
The long-term clinical efficacy of intraportal islet transplantation is hampered by islet loss due to inflammation, oxidative stress, and insufficient vascularization. This study explores the venous sac as an alternative implantation site for islet transplantation in large animal models.
Methods
An immunosuppressed, diabetic cynomolgus monkey received allogeneic islet implants in its mesenteric venous sac, with metabolic assessments over 112 days. Dogs underwent islet autotransplantation into various venous sacs, with their glycemic control and other metabolic parameters monitored for 1 month.
Results
In an nonhuman primate, the mesenteric venous sac site improved glycemic control over a 3-month period, followed by destabilization of graft function. Histologic studies revealed healthy islets. The lack of mononuclear cell infiltrate suggested no signs of graft rejection. Saphenous venous sacs in dogs showed superior glycemic control, reduced insulin requirements, and maintained C-peptide levels, comparable to intraportal transplantation. Histological analyses confirmed islet preservation and graft vascularization in saphenous venous sacs.
Conclusion
This study provides preclinical evidence in support of the venous sac as a valuable extrahepatic location for pancreatic islet implantation. We found that the saphenous vein is a more effective site for islet engraftment than the mesenteric vein. This study offers potential benefits for improving the success rates of clinical islet transplantation.

Cardiovascular Risk/Epidemiology
High Waist-to-Height Ratio Increases the Risk of Cardiovascular Outcomes in Adults with Type 1 Diabetes Mellitus: A Nationwide Cohort Study: Kyeong-Jin Kim, Seohyun Kim, Rosa Oh, So Hyun Cho, Myunghwa Jang, You-Bin Lee, Gyuri Kim, Sang-Man Jin, Kyu Yeon Hur, Ji Yoon Kim, Jae Hyeon Kim; Received March 4, 2025 Accepted June 21, 2025 Published online September 4, 2025; DOI: https://doi.org/10.4093/dmj.2025.0179 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Central obesity contributes to an increased risk of cardiovascular disease (CVD) and mortality. The waist-to-height ratio (WHtR) is a practical marker of central obesity across sexes, ages, and ethnicities. However, its association with comprehensive cardiovascular (CV) outcomes in patients with type 1 diabetes mellitus (T1DM) remains unclear.
Methods
From a nationwide cohort database (2006–2020), 16,928 Korean adults with T1DM were included. Participants were categorized by their WHtR values using three criteria: a three-group classification (<0.5, 0.5 to <0.6, and ≥0.6) and two binary classifications (≥0.5 vs. <0.5; ≥0.6 vs. <0.6). The primary outcomes were composite CV events, including heart failure (HF), myocardial infarction (MI), ischemic stroke, and CVD-related deaths, with each component analyzed as a secondary outcome.
Results
During a median follow-up of 6.7 years (interquartile range, 5.2 to 8.8), 4,293 composite CV events occurred. Compared to the WHtR <0.5 group, the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the composite CV outcome were 1.14 (1.05 to 1.24) in the WHtR 0.5 to <0.6 group and 1.62 (1.38 to 1.90) in the WHtR ≥0.6 group (P for trend <0.001). Increasing trends in aHRs were noted with rising WHtR values for each component of the composite outcome. Compared to the WHtR <0.6 group, the aHRs for the WHtR ≥0.6 group were as follows: HF, 1.49 (95% CI, 1.28 to 1.73); MI, 1.31 (95% CI, 1.02 to 1.68); ischemic stroke, 1.24 (95% CI, 1.02 to 1.51); and CVD-related death, 2.09 (95% CI, 1.49 to 2.92).
Conclusion
High WHtR is associated with an increased risk of CV events in adults with T1DM.

Brief Report

Technology/Device
Effectiveness of the Stage 4 Smart Insulin Pen DIA:CONN P8 for Glycemic Control in a Real-World Setting: So Yoon Kwon, Hyoseon Kwak, Jae Hyeon Kim; Received February 11, 2025 Accepted March 23, 2025 Published online September 3, 2025; DOI: https://doi.org/10.4093/dmj.2025.0112 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: This study evaluated whether a stage 4 smart insulin pen (SIP) provides superior glycemic control compared with a traditional insulin pen (TIP) in individuals with intensively insulin-treated diabetes. Forty-two adults with continuous glucose monitoring (CGM), multiple daily insulin injections, and no prior SIP use were included. After diabetes self-management education (DSME), the SIP group (n=21) initiated SIP, whereas the TIP group (n=21) continued their usual regimens. Glycemic metrics were assessed using CGM before and 2 weeks after DSME. Both groups demonstrated significant improvements in glycemic outcomes. However, SIP users exhibited superior improvements in the percentage of time in range, percentage of time below range (%TBR) <70 mg/dL, %TBR <54 mg/dL, and glycemic risk index compared with TIP users (between-group difference [BD] 11.0%, P=0.046; BD –2.6%, P=0.024; BD –0.9%, P=0.027; BD –18.2, P=0.022, respectively). These findings suggest that SIP, with its bolus calculation and CGM integration, is associated with improved glycemic outcomes in adults with intensively insulin-treated diabetes.

Reviews

Lifestyle and Behavioral Interventions
Clinically Practical and Affordable Lifestyle Modification to Prevent Diabetes Mellitus in Real Practice: Inji Lee, Minji Kang, Ji Hye Choi, Hyunjung Lim, Suk Chon; Diabetes Metab J. 2025;49(5):951-963. Published online September 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0675

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Abstract PDF PubReader ePub: As the prevalence of type 2 diabetes mellitus continues to rise, the development of effective and sustainable prevention strategies has become a critical public health priority. Evidence from large-scale randomized controlled trials has established that lifestyle modification (LSM) programs can substantially reduce the risk of diabetes in high-risk individuals. However, routine implementation is limited by high intensity, costs, and resource requirements. We summarize major prevention trials and their effectiveness, feasibility, and limitations. Building on these insights, we introduce the Korean Diabetes Prevention Study (KDPS) as a contextually tailored model for the Korean healthcare system. The KDPS-LSM program was designed to integrate cultural and clinical relevance with practical applicability, consisting of a 6-month intensive phase of structured nutrition and lifestyle education followed by a maintenance phase to support long-term adherence. To promote sustainable change, the program incorporates the ‘10 habit’ lifestyle messages, grounded in the transtheoretical model of behavior change, which are designed for easy implementation in daily life. This review underscores the importance of developing culturally appropriate LSM programs that balance effectiveness with feasibility, and suggests that the KDPS-LSM model could serve as a useful foundation for establishing practical diabetes prevention strategies within national healthcare systems.

Lifestyle and Behavioral Interventions
Management of Early-Onset Type 2 Diabetes in Adults: Current Evidence and Future Directions: Matthew J. Savage, Jonathan Goldney, Tommy Slater, Priscilla Sarkar, Jack A. Sargeant, Emma G. Wilmot, Melanie J. Davies; Diabetes Metab J. 2025;49(5):934-950. Published online September 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0561

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The global prevalence of early-onset type 2 diabetes (EOT2D) is rising rapidly. Adults with EOT2D represent a high-risk population characterised by increased rates of microvascular and macrovascular complications, adverse psychological wellbeing and psychiatric comorbidities such as depression, and premature mortality compared to those with later-onset type 2 diabetes mellitus. This emerging population faces unique challenges, including high levels of diabetes-related stigma, clinical inertia, and competing life demands, such as starting a family. This review synthesises current evidence on the clinical management of EOT2D. Key therapeutic targets include weight reduction, preservation of β-cell function, cardiometabolic risk management, and psychological support. Overall, there are few randomized controlled trials (RCTs) undertaken specifically in adults with EOT2D. However, we summarise early data from the few RCTs that do report outcomes specific in young adults, with bariatric surgery, tirzepatide and intensive lifestyle interventions emerging as particularly effective treatments. There is a strong rationale that technology-based inventions and structured education programs may prove to be effective treatments but data from RCTs is lacking. We provide broad recommendations for future research and clinical practice based on the current evidence. In conclusion, substantial further research is required to inform tailored, evidence-based guidelines and improve long-term outcomes in this underserved population.

Citations

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Identification of oral microbial biomarkers for prediabetes in young adults: A two-stage population-based study
Jiaqi Li, Guishao Tang, Zhiguo Xie, Lin Yang, Zhiguang Zhou, Keyu Guo
Diabetes Research and Clinical Practice.2026; 232: 113101. CrossRef

Original Articles

Others
The Concurrent Challenges of Sarcopenia and Frailty: A 5-Year Mortality Risk Evaluation in Geriatric Patients with Type 2 Diabetes Mellitus: Burcu Eren Cengiz, Nurhayat Tugra Ozer, Celil Barlas Cengiz, Yavuz Sultan Selim Akgul, Sibel Akın; Received January 30, 2025 Accepted June 12, 2025 Published online September 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0077 [Epub ahead of print]

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Abstract PDF PubReader ePub: Background
Type 2 diabetes mellitus (T2DM) is common among older adults and may increase the risk of sarcopenia and frailty. This study evaluates the impact of sarcopenia and frailty on 5-year mortality in older adults with T2DM.
Methods
We assessed a cohort study of 447 adults with T2DM who were more than 60 years old. To follow the guidelines set by the European Working Group on Sarcopenia in Older People 2 (EWGSOP 2), we used bioelectrical impedance analysis to measure muscle mass and a handgrip dynamometer to measure muscle strength. We assessed frailty using the Fatigue, Resistance, Ambulation, Illnesses, and Loss of weight (FRAIL) Scale. We categorised the patients into four groups: isolated sarcopenic, isolated alone, both conditions (sarcopenia and frailty), or neither.
Results
The mean age of the patients was 69 years, with 71.6% female. Isolated sarcopenic was present in 11.0%, isolated frail in 22.4%, and sarcopenia and frailty in 9.8%. After adjusting for variables such as age, sex, comorbidities, activities of daily living, glycemic control, and nutritional status, sarcopenia and frailty were found to be significantly associated with an increased risk of 5-year mortality. Isolated frail also significantly predicted mortality (hazard ratio, 2.59; 95% confidence interval, 1.34 to 5.03; P=0.005).
Conclusion
Sarcopenia and frailty are significant predictors of increased mortality risk in older adults with T2DM. Sarcopenia and frailty pose the highest risk. Early identification and targeted interventions for these conditions in older T2DM patients are crucial to improving outcomes.

Cardiovascular Risk/Epidemiology
E2F5 Accelerates Vascular Smooth Muscle Cells Phenotype Switching in Diabetic Atherosclerosis through Activating Wnt/β-Catenin Pathway: Mingxue Di, Jie Wang, Lin Sun, Guang Yang, Qun Xu; Received September 25, 2024 Accepted April 21, 2025 Published online September 1, 2025; DOI: https://doi.org/10.4093/dmj.2024.0588 [Epub ahead of print]

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Abstract PDF PubReader ePub: Background
We determined the precise function of E2F transcription factor 5 (E2F5) on the development of diabetic atherosclerosis (DAS) and the underlying mechanisms.
Methods
Apolipoprotein E-knockout mice were intraperitoneally injected streptozotocin for 5 days and fed a high-fat diet for 12 weeks for establishing an in vivo DAS model. To establish a DAS vascular smooth muscle cells (VSMCs) model, VSMCs were stimulated with fresh medium containing glucose and oxidized low-density lipoprotein. After the final treatment, serum lipids were detected, and aorta tissues were collected for hematoxylin and eosin staining, Western blot, Oil red O staining, and quantitative reverse transcription polymerase chain reaction. The effect of E2F5 on the proliferation, migration, cell cycle, phenotype switching, and cell cycle-related markers of VSMCs were evaluated.
Results
In vivo, the expression of E2F5 was elevated in aorta tissues of DAS mice. The downregulation of E2F5 alleviated the symptoms of DAS in mice. Moreover, E2F5 downregulation inhibited the phenotypic transformation of VSMCs in DAS mice. In vitro, the knockdown of E2F5 inhibited the phenotypic transformation of VSMCs. CyclinE overexpression reversed the inhibitory effect of E2F5 silencing on phenotypic transformation of VSMCs. Additionally, we also found that the treatment of BML-284 significantly attenuated the inhibitory effect of E2F5 silencing on phenotypic transformation of VSMCs.
Conclusion
E2F5 is an injurious factor in the pathogenesis of DAS, and the downregulation of E2F5 could repress VSMCs phenotype switching through inactivating Wnt/β-catenin pathway, and ultimately inhibit the progression of DAS.

Review

Complications
Diabetes Mellitus and Infectious Diseases: Current Evidence and Clinical Implications: Taeeun Kim, Sang-Ho Choi; Diabetes Metab J. 2025;49(5):915-933. Published online August 27, 2025; DOI: https://doi.org/10.4093/dmj.2025.0508

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Diabetes mellitus predisposes individuals to a broad spectrum of infections. People with diabetes face a 1.5- to 4-fold increased risk of both common and severe infections, and infections remain the leading cause of morbidity and mortality. Chronic hyperglycemia impairs neutrophil chemotaxis, oxidative burst, and complement activation, while vascular insufficiency and neuropathy compromise tissue perfusion and barrier integrity. These defects, together with altered skin, mucosal, and gut microbiota, influence the marked susceptibility to urinary tract infections (especially renal abscess and emphysematous pyelonephritis), osteomyelitis, diabetic foot infections, pneumonia (including influenza), tuberculosis, skin and soft tissue infections, and lifethreatening syndromes such as emphysematous cholecystitis and rhino-orbital mucormycosis that are almost exclusive to people with diabetes. Outcomes from infections are worse in diabetes. Although the core therapeutic principles align with those for patients without diabetes, management should be individualized. Glycemic control should balance infection risk and hypoglycemia; antimicrobial dosing should account for renal function and drug interactions; and strict antimicrobial stewardship is required. If needed, prompt debridement and multidisciplinary intervention are necessary to mitigate complications and reduce mortality. Preventive care relies on comprehensive vaccination (influenza, pneumococcus, severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], hepatitis B, herpes zoster, and Tdap/Td) and regular foot surveillance with offloading to avert ulceration.

Citations

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Review on the Gut‐Kidney Axis Mechanism and Therapeutic Strategies in Diabetic Nephropathy
Qing Li, Mingrong Cheng, Xiaoyan Zhang
Diabetes/Metabolism Research and Reviews.2026;[Epub] CrossRef
Prim-O-glucosylcimifugin targets Staphylococcus aureus caseinolytic protease P to inhibit α-hemolysin expression and promote healing of MRSA-induced diabetic skin infections
Yan Wang, Shanshan Luo, Xinping Guo, Mengli Jin, Xingye Wang, Mingran Li, Shuang Jiang, Lin Wei, Mingjun Liu, Wu Song
Microbial Pathogenesis.2026; 212: 108296. CrossRef
Preoperative triglyceride–glucose index as a metabolic predictor of surgical site infection after posterior lumbar fusion
Yu Hua, Shaoxing Li, Yuan Jiang, Jinwang Liu
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Development and validation of a risk nomogram model for predicting superficial fungal infections in patients with type 2 diabetes mellitus : a cross-sectional study
Yu Li, Guozhong Zhou, Feifei Yang, Rong long, Wei Shi, Yan Dong, Yuanyuan Zhou, Nan Chen, Ying Yang
BMC Infectious Diseases.2026;[Epub] CrossRef
Immunometabolic reprogramming in diabetic osteomyelitis: from mechanisms to therapeutics
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Frontiers in Cellular and Infection Microbiology.2025;[Epub] CrossRef
Risk of Acute Cholecystitis Based on Combination of Patient Age, Patient Sex, Leukocytosis, and Sonographic Murphy Sign
Hideaki Ishida, Hiroko Naganuma
Journal of Ultrasound in Medicine.2025;[Epub] CrossRef
Chronic Infections and Diabetes in Africa: A Narrative Review of Pathogen-Associated Metabolic Risk
Olabisi P Lawal, Fortune I Ebiala, Modinat Abayomi, Obiageri Ihuarulam Okeoma, Nana Ama Aduma Amankwah, John O Patrick, Queeneth Eguakun, Aliyu O Olaniyi
Cureus.2025;[Epub] CrossRef

Original Articles

Complications
Comparison of Efficacy and Safety of Cilostazol/Extract of Ginkgo biloba vs. Aspirin in Carotid Atherosclerosis in Patients with Diabetes Mellitus: You-Cheol Hwang, Mi Kyung Kim, Jung Hwan Park, Han Mi Yun, Sang Yong Kim, Soo Lim; Received February 24, 2025 Accepted May 16, 2025 Published online August 13, 2025; DOI: https://doi.org/10.4093/dmj.2025.0146 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
We conducted a prospective, randomized study to evaluate the combination of cilostazol (CTZ) and extract of Ginkgo biloba (EGb) and compare it with aspirin for the prevention of atherosclerosis progression in patients with type 2 diabetes mellitus (T2DM).
Methods
One hundred five patients with T2DM and increased carotid intima-media thickness (IMT) were randomly assigned to receive either CTZ 200 mg plus EGb 160 mg once daily or aspirin (ASA) 100 mg/day for 12 months. The primary endpoint was the change in maximum carotid IMT.
Results
The mean age and body mass index were 61.6±8.4 years and 25.2±3.1 kg/m² in the CTZ/EGb group and 61.6±7.6 years and 24.5±3.3 kg/m² in the ASA group, respectively. CTZ/EGb treatment reduced the maximum IMT in the bulb area (from 1.435±0.690 to 1.346±0.688 mm on the right; from 1.359±0.528 to 1.299±0.528 mm on the left), whereas ASA treatment did not, resulting in significant between-group differences (P<0.05). No significant differences were observed in the common carotid and internal carotid arteries. The CTZ/EGb group showed a reduction in triglycerides and an increase in high-density lipoprotein cholesterol levels. Additionally, aspartate and alanine aminotransferase levels decreased only in the CTZ/EGb group. There were no significant differences in Mini-Mental State Examination (MMSE) score changes or adverse events (ClinicalTrials.gov number: NCT05906199).
Conclusion
Twelve months of CTZ/EGb combination therapy significantly attenuated the progression of carotid atherosclerosis compared with aspirin in patients with T2DM.

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; Received December 20, 2024 Accepted May 6, 2025 Published online August 13, 2025; DOI: https://doi.org/10.4093/dmj.2024.0830 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub

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.

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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

Cardiovascular Risk/Epidemiology
Associations of Cardiocerebrovascular Risks and Exercise according to Menopausal Status in Women with Type 2 Diabetes Mellitus: A Nationwide Cohort Study: Ji-Hee Ko, Sun Joon Moon, Kyung-Do Han, Hye-Mi Kwon, Se-Eun Park, Eun-Jung Rhee, Won-Young Lee; Diabetes Metab J. 2026;50(1):101-114. Published online August 13, 2025; DOI: https://doi.org/10.4093/dmj.2024.0487

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Abstract PDF Supplementary Material PubReader ePub: Background
Menopausal status can increase the risk of cardiocerebrovascular diseases (CCVDs) in women with type 2 diabetes mellitus (T2DM). Regular exercise is well-known to reduce this risk. This study explored the impact of exercise on CCVD and mortality in women with T2DM according to their menopausal status.
Methods
A total of 32,477 premenopausal and 53,690 postmenopausal Korean women with T2DM aged 40 to 60 years from a national health examination cohort (2009 to 2018) were included. We evaluated risks for stroke, myocardial infarction (MI), and mortality based on exercise intensity. Cox proportional hazard regression analyses were performed to obtain the adjusted hazard ratio (aHR) and 95% confidence interval.
Results
Exercise reduced stroke, MI, and mortality risks in women with T2DM, regardless of menopausal status. The highest effects of aHR compared to the sedentary group were 0.68 for stroke, 0.66 for MI, and 0.81 for mortality. Postmenopausal women experienced significant MI risk reductions at most exercise intensities, with the greatest reduction in the ≥1,500 metabolic equivalent of task score group unlike premenopausal women. However, stroke and mortality risk reductions in postmenopausal women were less pronounced compared to premenopausal women.
Conclusion
Exercise reduces CCVD risk in women with T2DM across menopausal status. Postmenopausal women with T2DM had more benefits from exercise on MI but fewer benefits on stroke and mortality than premenopausal women. In premenopausal women with T2DM, exercise was not associated with a lower MI risk.

Basic and Translational Research
High-Fat Diet-Fed Kcnq1 Mutant Mice Have Reduced Pancreatic β-Cell Mass via Gene-Environment Interaction: Shun-ichiro Asahara, Hiroyuki Inoue, Yuka Ihara, Kyoko Teruyama, Asuka Imai, Chisako Hara, Mizuki Hara, Masako Seike, Aisha Yokoi, Nozomi Kido, Hirotaka Suzuki, Ayumi Kanno, Yuka Inaba, Hitoshi Watanabe, Go Shioi, Maki Kimura-Koyanagi, Michihiro Matsumoto, Hiroshi Inoue, Keiichi I. Nakayama, Wataru Ogawa, Masato Kasuga, Yoshiaki Kido; Diabetes Metab J. 2026;50(1):77-89. Published online July 30, 2025; DOI: https://doi.org/10.4093/dmj.2024.0790

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Abstract PDF Supplementary Material PubReader ePub: Background
The potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene has recently received much attention as a candidate susceptibility gene for type 2 diabetes mellitus, especially in Asian populations. We previously reported that Kcnq1 mutant mice exhibit reduced insulin secretion and hyperglycemia due to a decrease in pancreatic β-cell mass. Through in vivo and in vitro analyses, we ascertained that this mechanism is the result of the downregulation of the non-coding RNA ‘Kcnq1ot1,’ which is expressed in the paternal allele of the Kcnq1 gene region, causing an increase in the expression of the cell cycle inhibitor cyclin dependent kinase inhibitor 1C (Cdkn1c). It was found that decreased Kcnq1ot1 expression resulted in pancreatic β-cell failure; however, the degree of pancreatic β-cell volume reduction was not severe.
Methods
We induced obesity in Kcnq1ot1 truncation mice by feeding them a high-fat diet and evaluated pancreatic β-cell mass.
Results
In the present study, we reveal that CCAAT/enhancer binding protein beta (C/EBPβ), which is expressed at higher levels in pancreatic β-cells in obese individuals, further increases the expression of Cdkn1c, which is upregulated by the Kcnq1 gene mutation. We found that simultaneous Cdkn1c hypomethylation and C/EBPβ overexpression in pancreatic β-cells causes a synergistic decrease in pancreatic β-cell mass.
Conclusion
This finding suggests that the synergistic effect of genetic factors such as Kcnq1 gene mutations and environmental factors such as obesity and overeating, which lead to increased expression of C/EBPβ, contribute to the regulation of pancreatic β-cell mass. This study is the first to show that the Kcnq1 gene is related to pancreatic β-cell mass through genetic-environment interactions.

Pharmacotherapy
New Users of Sodium-Glucose Cotransporter 2 Inhibitors Are at Low Risk of Prostate Cancer: A Nationwide Cohort Study: Yun Kyung Cho, Sehee Kim, Myung Jin Kim, Woo Je Lee, Ye-Jee Kim, Chang Hee Jung; Diabetes Metab J. 2026;50(1):90-100. Published online July 22, 2025; DOI: https://doi.org/10.4093/dmj.2024.0693

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Background
Preclinical studies have reported anticancer properties of sodium-glucose cotransporter 2 inhibitors (SGLT2is). We aimed to elucidate the association between the use of SGLT2is and the risk of prostate cancer among male patients with type 2 diabetes mellitus (T2DM).
Methods
An active-comparator, new-user cohort design using a nationwide database between September 2014 and June 2020 was conducted on 45,601 new SGLT2i users and 205,395 new users of other glucose-lowering medications (oGLMs). In the following 1:1 propensity score matched (PSM) analysis, 35,371 SGLT2i users matched with an equivalent number of oGLM users were assessed. The hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer were calculated.
Results
Among the cohort, prostate cancer was diagnosed in 210 out of 45,601 SGLT2i users, corresponding to a cumulative incidence of 1.0%, in contrast to 1,880 cases among 205,395 users of oGLMs, with a cumulative incidence of 1.5%. The use of SGLT2is was significantly correlated with a reduced risk of prostate cancer based on a multivariable-adjusted HR of 0.83 (95% CI, 0.71 to 0.98). PSM analysis affirmed 18% reduction in prostate cancer risk associated with SGLT2i use (HR, 0.82; 95% CI, 0.67 to 0.99). Subgroup analyses revealed that body mass index (BMI) significantly influenced the effect of SGLT2i on prostate cancer risk, with a more pronounced reduction in the subgroup with a BMI <25 kg/m² (P=0.037).
Conclusion
The use of SGLT2is in Korean male patients with T2DM is associated with a lower risk of prostate cancer.

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Sodium-Glucose Cotransporter 2 Inhibitors as Emerging Anticancer Agents
Yun Kyung Cho, Chang Hee Jung
Diabetes & Metabolism Journal.2026; 50(1): 1. CrossRef

Metabolic Risk/Epidemiology
Metabolic Dysfunction-Associated Steatotic Liver Disease and Risk of Hepatocellular Carcinoma in Type 2 Diabetes Mellitus: So Hyun Cho, Gyuri Kim, Kyu-na Lee, Rosa Oh, Ji Yoon Kim, Myunghwa Jang, You-Bin Lee, Sang-Man Jin, Kyu Yeon Hur, Kyungdo Han, Jae Hyeon Kim; Diabetes Metab J. 2025;49(6):1298-1307. Published online July 22, 2025; DOI: https://doi.org/10.4093/dmj.2024.0641

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Background
We investigated the incidence rates of hepatocellular carcinoma (HCC) in metabolic dysfunction-associated steatotic liver disease (MASLD) categories, focusing on its association with alcohol consumption in patients with type 2 diabetes mellitus (T2DM).
Methods
This study included 2,418,858 patients with T2DM aged 20 years and older who underwent a health examination between 2009 and 2012. Participants were categorized into five groups according to hepatic steatosis, cardiometabolic risk factors, other liver diseases, and alcohol consumption. Hepatic steatosis was defined as the fatty liver index ≥30. Cox regression analysis was used to analyze the association between steatotic liver disease and development of HCC.
Results
The MASLD group showed a higher risk of HCC development regardless of alcohol consumption or presence of other liver diseases (adjusted hazard ratio [aHR], 1.38; 95% confidence interval [CI], 1.33 to 1.44). The MASLD with other combined group expressed the highest risk (aHR, 5.02; 95% CI, 4.79 to 5.27). In the metabolic dysfunction and alcohol-related steatotic liver disease and alcohol-related liver disease groups, heavy to excessive alcohol consumption increased the risk of HCC development, with a higher risk associated with greater alcohol intake (aHR, 2.40; 95% CI, 2.27 to 2.53 and aHR, 3.16; 95% CI, 2.93 to 3.41). Fine and Gray analysis also exhibited a consistent trend.
Conclusion
MASLD in patients with T2DM was associated with an increased risk of developing HCC, particularly when accompanied by other liver diseases. Moreover, alcohol consumption proportionally increased the risk of HCC with the amount of alcohol consumed.

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Telomere length and metabolic dysfunction-associated steatotic liver disease risk and progression: A systematic review and meta-analysis
Chunfeng Sun, Ping Qiu, Shuo Huang, Qihan Luo, Qing Ma, Piao Hu, Fangming Chen, Hongyan Wu, Chunxiao Chen
Experimental Gerontology.2026; 214: 113036. CrossRef

Metabolic Risk/Epidemiology
Risk Factors and Survival Outcomes of Immune Checkpoint Inhibitor-Induced Type 1 Diabetes Mellitus: A Retrospective Cohort Study: Sang-hyeok Go, Yun Kyung Cho, Eun Hee Koh; Diabetes Metab J. 2026;50(1):115-126. Published online July 22, 2025; DOI: https://doi.org/10.4093/dmj.2024.0455

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Abstract PDF PubReader ePub: Background
Immune checkpoint inhibitors (ICIs) have transformed the treatment of metastatic solid tumors; however, they induce immune-related adverse events, such as ICI-induced type 1 diabetes mellitus (ICI-T1DM), a rare but serious condition requiring lifelong insulin therapy. We aimed to identify the risk factors and survival outcomes associated with ICI-T1DM to optimize screening and mitigate adverse effects.
Methods
This retrospective cohort study analyzed 6,956 patients treated with ICIs at a tertiary care center between January 1, 2017, and February 28, 2023. ICI-T1DM was classified based on the need for persistent insulin therapy post-ICI and a C-peptide level <1.0 ng/mL. Patient demographics, clinical characteristics, treatment details, and survival outcomes were examined.
Results
ICI-T1DM was identified in 32 patients (0.46%) with a median onset time of 41 weeks. Significant risk factors included pre-existing diabetes (hazard ratio [HR], 2.352; 95% confidence interval [CI], 1.140 to 4.854), combination therapy with anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors (HR, 3.666; 95% CI, 1.224 to 10.979), prolonged ICI treatment (≥12 weeks; HR, 4.789; 95% CI, 1.806 to 12.701), and thyroid dysfunction (HR, 4.027; 95% CI, 1.847 to 8.779). ICI-T1DM occurrence and thyroid dysfunction were associated with improved survival (HR, 0.224; 95% CI, 0.093 to 0.539; and HR, 0.616; 95% CI, 0.566 to 0.670).
Conclusion
Patients with pre-existing diabetes, combined anti–PD-1/PD-L1 and anti–CTLA-4 therapy, prolonged ICI treatment (≥12 weeks), and thyroid dysfunction are at high risk of developing ICI-T1DM. The observed survival benefits in patients with ICI-T1DM underscore the importance of aggressive glucose monitoring and patient education for early detection and management.

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; Diabetes Metab J. 2025;49(4):565-579. Published online June 11, 2025; DOI: https://doi.org/10.4093/dmj.2025.0278

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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.

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GLP-1 Receptor Agonists: Advances in Mechanism, Therapeutic Applications, and Future Perspectives
Megha Pawar, Chandrashekhar Patil, Zubershaha Fakir, Durgesh Pagar, Sunil Mahajan
BioMed Target Journal.2025; : 2. CrossRef

Original Articles

Metabolic Risk/Epidemiology
Ultra-Processed Food Intake and Risk of Type 2 Diabetes Mellitus: A Dose-Response Meta-Analysis of Prospective Studies: Yujin Kim, Yoonkyoung Cho, Jin Eui Kim, Dong Hoon Lee, Hannah Oh; Diabetes Metab J. 2025;49(5):1064-1074. Published online June 9, 2025; DOI: https://doi.org/10.4093/dmj.2024.0706; Correction in: Diabetes Metab J 2026;50(1):211

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Background
Although some studies suggest a positive association between ultra-processed food (UPF) intake and type 2 diabetes mellitus (T2DM), little is known about the exact shape and risks associated with different units (percentage of g/day, absolute g/day, serving/day) of UPF intake and whether the association is independent of diet quality, total energy intake, and body mass index (BMI).
Methods
Prospective studies published through January 2024 were identified by searching PubMed, Embase, and Web of Science. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated using random-effects models. A nonlinear dose-response meta-analysis was conducted using restricted cubic spline analysis.
Results
After screening 569 publications, a total of 12 prospective cohort studies were included. Comparing the highest vs. lowest categories of intake, summary RR for T2DM risk was 1.48 (95% CI, 1.36 to 1.61). Higher summary RRs were observed among studies from Europe and North America. Among individual UPF subgroups, processed meats (summary RR, 1.34; 95% CI, 1.16 to 1.54) were positively associated, whereas ultra-processed cereals and breads (0.98; 95% CI, 0.97 to 0.99) and packaged savory snacks (0.92; 95% CI, 0.88 to 0.95) were inversely associated. The summary RRs associated with every 10% (of g/day), 100-g/day, and 1-serving/day increase in UPF intake were 1.14 (95% CI, 1.11 to 1.17), 1.05 (95% CI, 1.03 to 1.06), and 1.04 (95% CI, 1.03 to 1.05), respectively. The dose-response curve for absolute g/d intake suggested nonlinearity, showing a steeper risk increase approximately at >300 g/day. The associations persisted after adjustment for diet quality, energy intake, or BMI.
Conclusion
Our data suggest that UPF intake increases diabetes risk, with a potential threshold effect at 300 g/day.

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Ultra-Processed Food Intake and Risk of Type 2 Diabetes Mellitus: A Dose-Response Meta-Analysis of Prospective Studies (Diabetes Metab J 2025;49:1064-74)
Lirong Hu, Aiji Chen, Gang Tian
Diabetes & Metabolism Journal.2026; 50(1): 194. CrossRef
Ultra-Processed Food Intake and Risk of Type 2 Diabetes Mellitus: A Dose-Response Meta-Analysis of Prospective Studies (Diabetes Metab J 2025;49:1064-74)
Yujin Kim, Hannah Oh
Diabetes & Metabolism Journal.2026; 50(1): 208. CrossRef
Trends in sales of sugar-sweetened beverages and associated type 2 diabetes burden in nine African countries: an ecological time-series analysis
Caroline H. Karugu, Gershim Asiki, Senzo Mthembu, Samuel Iddi, Peter M. Kaberia, Shukri F. Mohamed, Richard E. Sanya, Sylvia Kiwuwa-Muyingo, Stefanie Vandevijvere, Charles Agyemang
Global Health Action.2025;[Epub] CrossRef

Cardiovascular Risk/Epidemiology
Comparative Efficacy of Initial Statin and Ezetimibe Combination versus Statin Monotherapy on Cardiovascular Outcomes in Diabetes Mellitus: A Nationwide Cohort Study: Minji Sohn, Young-Hwan Park, Soo Lim; Diabetes Metab J. 2025;49(6):1318-1330. Published online June 5, 2025; DOI: https://doi.org/10.4093/dmj.2024.0482

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Background
This study aimed to assess the efficacy of an initial combination therapy of statin and ezetimibe compared with statin monotherapy on major cardiovascular outcomes in individuals with diabetes.
Methods
In this population-based cohort study using National Health Insurance Service data (2010–2020), we included adults with diabetes who had not previously used any lipid-lowering medications. Those initiating statin monotherapy were matched 1:1 using propensity scores with patients starting combination therapy with a lower-potency statin and ezetimibe. This matching process resulted in 21,458 individuals in the primary prevention cohort and 10,094 in the secondary prevention cohort, respectively. The primary endpoint was a composite of myocardial infarction, stroke, and cardiovascular death. Hospitalizations for heart failure, angina, and all-cause mortality were analyzed. The impact of ezetimibe maintenance on the primary endpoint was analyzed, and other hospitalizations were categorized as adverse events.
Results
Compared with statin monotherapy, statin-ezetimibe combination significantly reduced the incidence of the primary endpoint (4.85 vs. 3.25 per 1,000 person-years: hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.56 to 0.81 in the primary cohort; and 19.5 vs. 15.7 per 1,000 person-years: HR, 0.80; 95% CI, 0.70 to 0.91 in the secondary cohort) and myocardial infarction (HR, 0.64; 95% CI, 0.46 to 0.82 in the primary cohort; and HR, 0.73; 95% CI, 0.60 to 0.89 in the secondary cohort). A longer maintenance period of ezetimibe was significantly related to better efficacy in the composite cardiovascular outcomes. High-intensity statin monotherapy was associated with an elevated risk of liver, muscle, and diabetes-related hospitalization in the primary prevention cohort.
Conclusion
Initial therapy with a statin-ezetimibe combination is associated with a reduced risk of cardiovascular events and fewer adverse events compared to statin monotherapy in individuals with diabetes, over a mean follow-up of 5.5 years (up to 9 years).

Citations

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Cardiovascular outcomes and adverse drug reactions associated with the use of ezetimibe in combination with a statin in diabetes mellitus patients with higher risk for myocardial infarction: a meta-analysis
Yan Zhou, Ji Jin
BMC Cardiovascular Disorders.2026;[Epub] CrossRef
Sirtuins and regulatory miRNAs as epigenetic determinants of empagliflozin-mediated recovery after acute myocardial infarction
Anna Nowak-Szwed, Ceren Eyileten, Zofia Wicik, Sara Ahmadova, Jeff Palatini, Jolanta Siller-Matula, Dirk von Lewinski, Harald Sourij, Marek Postula
Cardiovascular Diabetology.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.

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; Diabetes Metab J. 2025;49(6):1204-1218. Published online May 22, 2025; DOI: https://doi.org/10.4093/dmj.2024.0532

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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.

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Sappanone A, a potential natural inhibitor of PI3K, alleviates metabolic dysfunction-associated steatohepatitis in experimental models
Xi Qiao, Qian Li, Ruiqi Fan, Yujie Cheng, Qingxuan Zeng, Huan Xue, Xiaoli Zhang, Yi Zhang, Yunfeng Liu
Biochemical Pharmacology.2025; 242: 117305. CrossRef
Cell-specific roles of autophagy in liver fibrosis: implications for targeted pharmacotherapy
Chibo Liu, Huan Yang, Yongjie Liu, Min An, Zhiyong Weng, Lihua Li
Annals of Medicine.2025;[Epub] CrossRef

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; Diabetes Metab J. 2025;49(6):1229-1241. Published online May 22, 2025; DOI: https://doi.org/10.4093/dmj.2024.0339

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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.

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Microneedle strategies for diabetic wound management: A comprehensive review of materials, mechanisms, and therapeutic outcomes
Kaustubh Naik, Kanhaiya Singh
Materials Today Advances.2026; 29: 100684. CrossRef

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; Diabetes Metab J. 2025;49(6):1287-1297. Published online May 21, 2025; DOI: https://doi.org/10.4093/dmj.2024.0601

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Abstract PDF Supplementary Material PubReader ePub: 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; Diabetes Metab J. 2025;49(5):1106-1115. Published online May 21, 2025; DOI: https://doi.org/10.4093/dmj.2024.0406

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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.

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Impact of Remnant Cholesterol on the Risk for End-Stage Renal Disease in Type 2 Diabetes Mellitus: A Nationwide Population-Based Cohort Study (Diabetes Metab J 2025;49:1106-15)
Jun Hwa Hong
Diabetes & Metabolism Journal.2026; 50(1): 190. CrossRef

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; Diabetes Metab J. 2025;49(6):1272-1286. Published online May 21, 2025; DOI: https://doi.org/10.4093/dmj.2024.0319

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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.

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The Relationship Between High-Density Lipoprotein (HDL) and Glycated Hemoglobin (HbA1C) in Type 2 Diabetes Mellitus Patients: Implications for Cardiovascular Risk
Setyoadi Setyoadi, Dina Dewi Sartika Lestari Ismail, Annisa Wuri Kartika, Dewi Purnama Sari, Angel Dwi Septian, Adelina Stefanie Lallo, Rara Kurniasari
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Reviews

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

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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.

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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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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.

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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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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.

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Zoubiri Houda, Saiah Wassila, Otmane Amel, Saidi Hamza, Makrelouf Mohamed, Aitabderrhmane Samir, Haddam Ali El Mahdi, Koceir Elhadj-Ahmed
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Original Articles

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; Diabetes Metab J. 2025;49(6):1252-1261. Published online April 29, 2025; DOI: https://doi.org/10.4093/dmj.2024.0660

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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.

Citations

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LASSBio-1986 as a Multifunctional Antidiabetic Lead: SGLT1/2 Docking, Redox–Inflammatory Modulation and Metabolic Benefits in C57BL/6 Mice
Landerson Lopes Pereira, Raimundo Rigoberto B. Xavier Filho, Gabriela Araújo Freire, Caio Bruno Rodrigues Martins, Maurício Gabriel Barros Perote, Cibelly Loryn Martins Campos, Manuel Carlos Serrazul Monteiro, Isabelle de Fátima Vieira Camelo Maia, Renata
International Journal of Molecular Sciences.2026; 27(2): 829. CrossRef

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; Diabetes Metab J. 2025;49(5):1040-1050. Published online April 28, 2025; DOI: https://doi.org/10.4093/dmj.2024.0804

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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.

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Association of perceived diabetes stigma with time below range <3.0 mmol/L and anxiety in adults with type 1 diabetes using continuous glucose monitoring
Seohyun Kim, Soojin Park, Sang‐Man Jin, Jae Hyeon Kim, Gyuri Kim
Diabetic Medicine.2026;[Epub] CrossRef
Sequential use of continuous glucose monitoring, with or without exercise trackers, significantly improves glycemic control in patients with type 2 diabetes
Anushka Lahiri, Suan Tee Lim, Htike Kyu, Yock Young Dan, Chin Meng Khoo
Diabetology & Metabolic Syndrome.2025;[Epub] CrossRef
Efficacy and Safety of Stage 5 Connected Insulin Pens in Type 1 or Type 2 Diabetes: Randomized Controlled Trial Protocol
Ji Yoon Kim, Nam Hoon Kim, Soo Heon Kwak, Chang Hee Jung, Eun Seok Kang, Jun Sung Moon, Sun Joon Moon, So Yoon Kwon, Jee Hee Yoo, Younghoon Kim, Tae-min Lee, Chung-il Yang, Jae Hyeon Kim, Sang-Man Jin
Endocrinology and Metabolism.2025;[Epub] CrossRef

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; Diabetes Metab J. 2025;49(4):862-872. Published online April 5, 2025; DOI: https://doi.org/10.4093/dmj.2024.0578

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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.

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Elevated triglyceride‐glucose index is associated with increased risk of chronic kidney disease and end‐stage renal disease in type 1 diabetes: Nationwide cohort study
Rosa Oh, Seohyun Kim, So Hyun Cho, Ji Yoon Kim, Myunghwa Jang, Sang Ho Park, You‐Bin Lee, Sang‐Man Jin, Kyu Yeon Hur, Gyuri Kim, Jae Hyeon Kim
Diabetes, Obesity and Metabolism.2026;[Epub] CrossRef

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; Diabetes Metab J. 2025;49(5):1051-1063. Published online March 26, 2025; DOI: https://doi.org/10.4093/dmj.2024.0507

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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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Early Enrollment in Diabetes Pay-for-Performance Program Reduced Loss of Life Expectancy in Newly-Diagnosed Patients with Type 2 Diabetes Mellitus (Diabetes Metab J 2025;49:1051-63)
Fatima Qazi, Salahuddin Qazi
Diabetes & Metabolism Journal.2026; 50(1): 192. CrossRef
Early Enrollment in Diabetes Pay-for-Performance Program Reduced Loss of Life Expectancy in Newly-Diagnosed Patients with Type 2 Diabetes Mellitus (Diabetes Metab J 2025;49:1051-63)
Yu-Ching Chen, Wei-Ming Wang, Boniface J. Lin, Jung-Der Wang, Li-Jung Elizabeth Ku
Diabetes & Metabolism Journal.2026; 50(1): 205. CrossRef
Start Early, Do It Well: Implications of a National Diabetes Care Quality Assessment Program for Life Expectancy
Kyoung Hwa Ha, Dae Jung Kim
Diabetes & Metabolism Journal.2025; 49(5): 987. CrossRef

Others
Fibroblast Growth Factor 21 Levels Are Associated With Perception and Neural Responses to Sweetness in Type 2 Diabetes Mellitus: Piao Kang, Ying Zhang, Dian Zeng, Dan Liu, Rui Han, Yuwei Lu, Di Cheng, Qinyi Wang, Silin Liu, Liang Wu, Qian Wu, Shujie Yu, Anran Chen, Jingyi Guo, Wenli Ge, Jiacheng Ni, Jingyi Yang, Xiaomeng Wu, Lifei Ma, Weiping Jia, Qichen Fang, Yuehua Li, Huating Li; Diabetes Metab J. 2025;49(4):893-905. Published online March 26, 2025; DOI: https://doi.org/10.4093/dmj.2024.0390

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Background
The relationship between fibroblast growth factor 21 (FGF21) and sweet taste perception and preference in type 2 diabetes mellitus (T2DM) remains unclear. This study aims to investigate this relationship and examine the neural responses of T2DM patients to high-calorie sweet (HCS) food pictures, further exploring its correlation with FGF21 levels.
Methods
We assessed sweet taste perception and preference in 40 T2DM patients and 41 controls using classical scales. Subsequently, the neural responses of 11 T2DM patients and 11 controls to HCS pictures were examined using functional magnetic resonance imaging. FGF21 levels were measured using chemiluminescent immunoassay, and the correlations with taste perception and neural responses were analyzed.
Results
Increased FGF21 levels were associated with decreased sweet perception and increased sweet taste preference in T2DM patients. Compared to control, T2DM patients exhibited greater neural activations in the orbitofrontal cortex, anterior cingulate cortex (ACC), thalamus, and hippocampus (HCS vs. non-food) as well as the putamen (HCS vs. low-calorie food). Notable differences were observed in the parahippocampal gyrus, insula, ACC, and hippocampus in T2DM patients (HCS vs. high-calorie non-sweet). Additionally, FGF21 accounted for 30.39% and 32.4% of the associations between T2DM and ACC, and parahippocampal gyrus, respectively.
Conclusion
FGF21 levels were independently associated with changes in sweet taste perception and preference in T2DM patients and were significantly associated with activation in reward-related brain regions. This study reveals the potential role of FGF21 in regulating responses to sweet foods in T2DM and provides insight to develop new therapeutic strategies for diabetes.

Citations

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Exploring Biomarkers in Type 2 Diabetes Mellitus versus Normoglycemia Identified through High-Throughput Proteomics: A Systematic Review and Meta-Analysis
Julia García-Currás, Raquel Pérez-Lois, Guillermo L. Taboada, María P. Pata
Journal of Proteome Research.2026; 25(1): 4. CrossRef

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