Diabetes & Metabolism Journal

Original Articles

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

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

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

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

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

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

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

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

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

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

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

Basic and Translational Research
Extracellular Vesicle-Mediated Network in the Pathogenesis of Obesity, Diabetes, Steatotic Liver Disease, and Cardiovascular Disease: Joonyub Lee, Won Gun Choi, Marie Rhee, Seung-Hwan Lee; Diabetes Metab J. 2025;49(3):348-367. Published online May 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0184

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Abstract PDF PubReader ePub: Extracellular vesicles (EVs) are lipid bilayer-enclosed particles carrying bioactive cargo, including nucleic acids, proteins, and lipids, facilitating intercellular and interorgan communication. In addition to traditional mediators such as hormones, metabolites, and cytokines, increasing evidence suggests that EVs are key modulators in various physiological and pathological processes, particularly influencing metabolic homeostasis and contributing to the progression of cardiometabolic diseases. This review provides an overview of the most recent insights into EV-mediated mechanisms involved in the pathogenesis of obesity, insulin resistance, diabetes mellitus, steatotic liver disease, atherosclerosis, and cardiovascular disease. EVs play a critical role in modulating insulin sensitivity, glucose homeostasis, systemic inflammation, and vascular health by transferring functional molecules to target cells. Understanding the EV-mediated network offers potential for identifying novel biomarkers and therapeutic targets, providing opportunities for EV-based interventions in cardiometabolic disease management. Although many challenges remain, this evolving field highlights the need for further research into EV biology and its translational applications in cardiovascular and metabolic health.

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

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

Original Articles

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

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

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

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

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

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

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

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

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; Received July 17, 2024 Accepted December 3, 2024 Published online March 26, 2025; DOI: https://doi.org/10.4093/dmj.2024.0390 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: 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.

Basic Research
Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat: Serena Boccella, Andrea Maria Morace, Cristina Giorgio, Francesca Guida, Michela Perrone, Iolanda Manzo, Carmela Belardo, Meghan Jones, Sabatino Maione, Andrea Aramini, Marcello Allegretti, Livio Luongo, Laura Brandolini; Received August 25, 2024 Accepted November 15, 2024 Published online March 12, 2025; DOI: https://doi.org/10.4093/dmj.2024.0504 [Epub ahead of print]

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Abstract PDF PubReader ePub: Background
The CXC motif chemokine ligand 8 (CXCL8)-CXC motif chemokine receptor 1/2 (CXCR1/2) axis has been implicated in type 1 diabetes mellitus (T1DM). Its actions on non-immune cells may also contribute to T1DM-associated complications, including painful diabetic peripheral neuropathy (DPN) and diabetic retinopathy (DR).
Methods
We assessed the efficacy of early (4–8 weeks) or late (8–12 weeks) daily ladarixin (LDX) for the treatment of streptozotocin (STZ)-induced T1DM and the related complications of DPN or DR in male rats.
Results
Early LDX mitigated STZ-induced dysmetabolism (i.e., blood glucose, insulin), inflammation in dorsal root ganglion/ sciatic nerve (interleukin-1β and tumor necrosis factor-α expression) and mechanical allodynia and thermal hyperalgesia, indicative of DPN. Moreover, vitreous citrullinated histone H3 (CitH3) and plasma GRO/CINC1 (CXCL8) increase were attenuated. Late LDX failed to reverse STZ-induced changes in metabolic parameters (i.e., blood glucose, insulin, C-peptide, pancreatic β-cell number and function). Strikingly, even in the absence of an effect on glycemic control, late LDX mitigated STZ-induced mechanical allodynia and thermal hyperalgesia and vitreous (CXCL8, CitH3) and retinal (CXCL8, CXCR1/2, myeloperoxidase, CitH3) inflammatory/pro-angiogenic (vascular endothelial growth factor, CD34) signs of DR.
Conclusion
These data confirm the efficacy of LDX in STZ-induced T1DM and provide evidence of a protective effect also against DPN and onset of DR which is independent of its effect on β-cell functionality preservation and glycemic control.

Complications
Global, Regional, and National Temporal Trends in Incidence for Type 2 Diabetes Mellitus Related Chronic Kidney Disease from 1992 to 2021: Yu Cao, Huiting Chen, Hui Liu, Hao Wu, Wei Gao; Received September 26, 2024 Accepted November 21, 2024 Published online March 11, 2025; DOI: https://doi.org/10.4093/dmj.2024.0593 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Type 2 diabetes mellitus (T2DM) is a major cause of declining renal function.
Methods
Temporal trends in T2DM-related chronic kidney disease (CKD-T2DM) incidence across 204 countries and territories from 1992 to 2021 were analyzed using data from the Global Burden of Disease 2021. The impact of macro-factors (demographic change, age, period, and birth cohort) on CKD-T2DM incidence trends was assessed using decomposition analyses and age-period- cohort modeling, highlighting opportunities to improve incidence and reduce regional disparities.
Results
In 2021, global CKD-T2DM incidence cases reached 2.01 million, a 150.92% increase since 1992, with population growth and aging contributing to 80% of this rise. The age-standardized incidence rate (ASIR) ranged from 15.09 per 100,000 in low sociodemographic index (SDI) regions to 23.07 in high SDI regions. China, India, the United States, and Japan have the most incidence cases, accounted for 69% of incidence cases globally. With 175 countries showing an increasing ASIR trend. Unfavorable trend in ASIR increase were generally found in most high-middle and middle SDI countries, such as China and Mexico (net drift=0.15% and 1.17%, per year). Age-period-cohort analyses indicated a high incidence risk near age 80, with worsening risks for recent periods and birth cohorts, except in high SDI areas.
Conclusion
The CKD-T2DM incidence burden continues to rise globally, with significant variations between countries, posing major global health implications. CKD-T2DM is largely preventable and treatable, warranting greater attention in global health policy, particularly for older populations and in low and middle SDI regions.

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