Depressive tendencies associated with difficulty in the treatment of type 1 diabetes (T1D) could hinder appropriate intervention. Factors related to depressive tendencies in Japan remain unclear, though recent advances in medication may have affected them.
Materials and methods
Three hundred and fifty-two Japanese patients with T1D registered in the Juntendo-Aso Type 1 Diabetes (JAT-1) Cohort Study were divided into two groups based on depressive tendencies assessed with the Beck Depression Inventory-II score. We compared background characteristics of the patients between the groups and also analyzed additional clinical factors and quality of life scores.
Results
The patients with a Beck Depression Inventory-II score ≧14 (35.5%) are classified as having depressive tendencies. Compared to the individuals without depressive characteristics, those with depressive tendencies had significantly higher proportions of females, welfare recipients, and shift workers; a higher proportion of individuals with microvascular complications; higher diastolic pressure; eating out or taking out food more frequently for dinner; lower protein intake; and higher scores in the total score of diabetes-related problem domains and Pittsburgh Sleep Quality Index. Multiple regression analysis revealed that diastolic blood pressure, welfare recipient status, total score of diabetes-related problem domains (PAID), and Pittsburgh Sleep Quality Index were significantly associated factors with BDI-II score, and the PAID score showed the strongest association.
Conclusions
This study revealed that diabetes-specific psychological burden, evaluated with the PAID score, is strongly associated with depressive tendencies. Routine use of the PAID could support the strategies to prevent depression in people with type 1 diabetes by identifying those at risk.
{"title":"The Beck Depression Inventory-II scores of adults with type 1 diabetes in Japan: Analysis using the Juntendo-Aso Type 1 Diabetes (JAT-1) Cohort","authors":"Fuki Ikeda, Junko Sato, Kenichi Nakajima, Mami Koshibu, Ayako Sato, Katsumi Aso, Yuya Nishida, Hirotaka Watada","doi":"10.1111/jdi.70151","DOIUrl":"10.1111/jdi.70151","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Depressive tendencies associated with difficulty in the treatment of type 1 diabetes (T1D) could hinder appropriate intervention. Factors related to depressive tendencies in Japan remain unclear, though recent advances in medication may have affected them.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and methods</h3>\u0000 \u0000 <p>Three hundred and fifty-two Japanese patients with T1D registered in the Juntendo-Aso Type 1 Diabetes (JAT-1) Cohort Study were divided into two groups based on depressive tendencies assessed with the Beck Depression Inventory-II score. We compared background characteristics of the patients between the groups and also analyzed additional clinical factors and quality of life scores.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The patients with a Beck Depression Inventory-II score ≧14 (35.5%) are classified as having depressive tendencies. Compared to the individuals without depressive characteristics, those with depressive tendencies had significantly higher proportions of females, welfare recipients, and shift workers; a higher proportion of individuals with microvascular complications; higher diastolic pressure; eating out or taking out food more frequently for dinner; lower protein intake; and higher scores in the total score of diabetes-related problem domains and Pittsburgh Sleep Quality Index. Multiple regression analysis revealed that diastolic blood pressure, welfare recipient status, total score of diabetes-related problem domains (PAID), and Pittsburgh Sleep Quality Index were significantly associated factors with BDI-II score, and the PAID score showed the strongest association.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study revealed that diabetes-specific psychological burden, evaluated with the PAID score, is strongly associated with depressive tendencies. Routine use of the PAID could support the strategies to prevent depression in people with type 1 diabetes by identifying those at risk.</p>\u0000 </section>\u0000 </div>","PeriodicalId":51250,"journal":{"name":"Journal of Diabetes Investigation","volume":"16 11","pages":"2111-2117"},"PeriodicalIF":3.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jdi.70151","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
High 1-h plasma glucose levels have an increased risk of type 2 diabetes. To determine the pathophysiological features in participants with normal glucose tolerance (NGT) with 1-h hyperglycemia (HG), we investigated the variability in the glucagon and insulin secretions after oral glucose loading and nutrient survey.
Materials and Methods
A 75-g oral glucose tolerance test (OGTT) was performed in Japanese Americans (aged 40–75 years), enrolled in medical surveys conducted in 2015. We recruited only participants with NGT defined as fasting glucose values <110 mg/dL and 2-h glucose levels <140 mg/dL. We evaluated homeostatic model assessment for insulin resistance (HOMA-IR), insulin sensitivity index (MATSUDA-Index), insulin, and glucagon (GCG) secretions during the 75-g OGTT and compared them between 1-h serum glucose values: <155 mg/dL (1-h non-hyperglycemia: NHG, n = 76) and 1-h serum glucose values: ≥155 mg/dL (HG, n = 41). We also conducted a dietary intake survey to determine the association between 1-h serum glucose and nutritional intake in the usual diet.
Results
The HG group demonstrated significant insulin resistance compared to the NHG group. Two-h GCG levels were significantly lower in the HG group. Additionally, low vegetable fat intake was significantly associated with 1-h HG after adjusting for sex, age, and body mass index.
Conclusions
Insulin resistance is already present in the HG group. Vegetable fat intake may be associated with glucose metabolism regardless of clinical background.
目的/介绍：1-h血浆葡萄糖水平高会增加2型糖尿病的风险。为了确定糖耐量正常（NGT）伴有1小时高血糖（HG）的受试者的病理生理特征，我们研究了口服葡萄糖负荷和营养调查后胰高血糖素和胰岛素分泌的变异性。材料与方法：对2015年开展医学调查的日裔美国人（40-75岁）进行75 g口服葡萄糖耐量试验（OGTT）。我们只招募了空腹血糖值定义为NGT的参与者。结果：与NHG组相比，HG组表现出明显的胰岛素抵抗。HG组2 h GCG水平明显降低。此外，在调整性别、年龄和体重指数后，低植物脂肪摄入量与1-h HG显著相关。结论：HG组已经存在胰岛素抵抗。无论临床背景如何，植物脂肪摄入可能与葡萄糖代谢有关。
{"title":"Clinical characteristics of Japanese Americans with normal glucose tolerance with 1-h hyperglycemia: A cross-sectional study","authors":"Natsumi Himeno, Tsuguka Matsuda, Yoshimi Morita, Takaya Kodama, Ryuta Baba, Gentaro Egusa, Gaku Nagano, Noboru Hattori, Haruya Ohno","doi":"10.1111/jdi.70148","DOIUrl":"10.1111/jdi.70148","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims/Introduction</h3>\u0000 \u0000 <p>High 1-h plasma glucose levels have an increased risk of type 2 diabetes. To determine the pathophysiological features in participants with normal glucose tolerance (NGT) with 1-h hyperglycemia (HG), we investigated the variability in the glucagon and insulin secretions after oral glucose loading and nutrient survey.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and Methods</h3>\u0000 \u0000 <p>A 75-g oral glucose tolerance test (OGTT) was performed in Japanese Americans (aged 40–75 years), enrolled in medical surveys conducted in 2015. We recruited only participants with NGT defined as fasting glucose values <110 mg/dL and 2-h glucose levels <140 mg/dL. We evaluated homeostatic model assessment for insulin resistance (HOMA-IR), insulin sensitivity index (MATSUDA-Index), insulin, and glucagon (GCG) secretions during the 75-g OGTT and compared them between 1-h serum glucose values: <155 mg/dL (1-h non-hyperglycemia: NHG, <i>n</i> = 76) and 1-h serum glucose values: ≥155 mg/dL (HG, <i>n</i> = 41). We also conducted a dietary intake survey to determine the association between 1-h serum glucose and nutritional intake in the usual diet.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The HG group demonstrated significant insulin resistance compared to the NHG group. Two-h GCG levels were significantly lower in the HG group. Additionally, low vegetable fat intake was significantly associated with 1-h HG after adjusting for sex, age, and body mass index.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Insulin resistance is already present in the HG group. Vegetable fat intake may be associated with glucose metabolism regardless of clinical background.</p>\u0000 </section>\u0000 </div>","PeriodicalId":51250,"journal":{"name":"Journal of Diabetes Investigation","volume":"16 11","pages":"2018-2026"},"PeriodicalIF":3.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jdi.70148","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>The global burden of type 2 diabetes continues to rise, driven by population aging, urbanization, and the increasing prevalence of obesity and sedentary lifestyles. In Asia, including Japan, Korea, and China, the rapid pace of change in dietary and physical activity patterns has created a parallel surge in diabetes prevalence, making prevention an urgent priority<span><sup>1</sup></span>. Despite significant progress in glucose-lowering therapies, the most cost-effective and sustainable approach remains preventing diabetes before it develops. Few studies have shaped this field more profoundly than the Diabetes Prevention Program (DPP) and its long-term follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS). The DPP, published in 2002, demonstrated that intensive lifestyle intervention reduced the incidence of type 2 diabetes by 58% and metformin by 31% over 3 years compared with placebo<span><sup>2</sup></span>. These results established lifestyle modification as the gold standard for diabetes prevention and validated metformin as an adjunct option in selected individuals. These findings became the cornerstone of diabetes prevention strategies worldwide. Yet a critical question has remained: Are the benefits of these interventions durable over the long term?</p><p>In their recent publication in <i>The Lancet Diabetes & Endocrinology</i>, Knowler <i>et al</i>.<span><sup>3</sup></span> provide a long-term perspective of the DPP cohort, with follow-up extending approximately 21 years. Compared with placebo, diabetes incidence rate was reduced by 24% in the intensive lifestyle intervention group and by 17% in the metformin group, with a corresponding delay in diabetes onset by a median of 3.5 and 2.5 years (Table 1). Both interventions reduced cumulative diabetes incidence, although the absolute risk differences narrowed over time. The critical insight is that most of the benefit accrued during the first 3 years of the trial, when intervention intensity and adherence were highest. The curves diverged early and remained separated, demonstrating a “legacy effect” that persisted for two decades. This long-term durability reinforces a central principle of prevention that early and intensive interventions leave a lasting imprint on disease trajectories. Similar patterns were observed in the Da Qing study in China, where modest lifestyle changes implemented over 6 years translated into lower rates of diabetes and cardiovascular events over 30 years<span><sup>4</sup></span>. In that trial, 577 adults with impaired glucose tolerance were randomized to diet, exercise, diet plus exercise, or control. After 6 years of intervention, diabetes incidence was significantly reduced in the lifestyle groups compared with control. Importantly, long-term follow-up over 30 years revealed not only a persistent reduction in diabetes risk but also meaningful clinical outcomes: a 26% lower incidence of cardiovascular disease, a 35% reduction in microvascular
{"title":"Two decades of diabetes prevention: Sustained benefits, heterogeneous effects, and implications for precision prevention","authors":"Seung-Hwan Lee","doi":"10.1111/jdi.70150","DOIUrl":"10.1111/jdi.70150","url":null,"abstract":"<p>The global burden of type 2 diabetes continues to rise, driven by population aging, urbanization, and the increasing prevalence of obesity and sedentary lifestyles. In Asia, including Japan, Korea, and China, the rapid pace of change in dietary and physical activity patterns has created a parallel surge in diabetes prevalence, making prevention an urgent priority<span><sup>1</sup></span>. Despite significant progress in glucose-lowering therapies, the most cost-effective and sustainable approach remains preventing diabetes before it develops. Few studies have shaped this field more profoundly than the Diabetes Prevention Program (DPP) and its long-term follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS). The DPP, published in 2002, demonstrated that intensive lifestyle intervention reduced the incidence of type 2 diabetes by 58% and metformin by 31% over 3 years compared with placebo<span><sup>2</sup></span>. These results established lifestyle modification as the gold standard for diabetes prevention and validated metformin as an adjunct option in selected individuals. These findings became the cornerstone of diabetes prevention strategies worldwide. Yet a critical question has remained: Are the benefits of these interventions durable over the long term?</p><p>In their recent publication in <i>The Lancet Diabetes & Endocrinology</i>, Knowler <i>et al</i>.<span><sup>3</sup></span> provide a long-term perspective of the DPP cohort, with follow-up extending approximately 21 years. Compared with placebo, diabetes incidence rate was reduced by 24% in the intensive lifestyle intervention group and by 17% in the metformin group, with a corresponding delay in diabetes onset by a median of 3.5 and 2.5 years (Table 1). Both interventions reduced cumulative diabetes incidence, although the absolute risk differences narrowed over time. The critical insight is that most of the benefit accrued during the first 3 years of the trial, when intervention intensity and adherence were highest. The curves diverged early and remained separated, demonstrating a “legacy effect” that persisted for two decades. This long-term durability reinforces a central principle of prevention that early and intensive interventions leave a lasting imprint on disease trajectories. Similar patterns were observed in the Da Qing study in China, where modest lifestyle changes implemented over 6 years translated into lower rates of diabetes and cardiovascular events over 30 years<span><sup>4</sup></span>. In that trial, 577 adults with impaired glucose tolerance were randomized to diet, exercise, diet plus exercise, or control. After 6 years of intervention, diabetes incidence was significantly reduced in the lifestyle groups compared with control. Importantly, long-term follow-up over 30 years revealed not only a persistent reduction in diabetes risk but also meaningful clinical outcomes: a 26% lower incidence of cardiovascular disease, a 35% reduction in microvascular","PeriodicalId":51250,"journal":{"name":"Journal of Diabetes Investigation","volume":"16 10","pages":"1779-1781"},"PeriodicalIF":3.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jdi.70150","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We aimed to explore associations between Red cell distribution width (RDW), RDW to albumin ratio (RAR), and long-term all-cause and cardiovascular disease (CVD) mortality in adults with diabetes and DN.
Methods
This study included adults aged ≥40 years with DN from the National Health and Nutrition Examination Survey from 1999 to 2004, followed through 2019. Cox proportional hazards models were used to assess associations between RDW, RAR, and all-cause and CVD mortality. Predictive accuracy was determined using area under the curve (AUC) by receiver operating characteristic analyses.
Results
Data of a total of 624 participants with DN were analyzed. Each unit increase in RDW significantly increased all-cause mortality by 12% (adjusted hazard ratio (aHR) = 1.12, 95% CI: 1.05–1.20) and CVD mortality by 15% (aHR = 1.15, 95% CI: 1.02–1.31), while each unit increase in RAR increased all-cause mortality by 73% (aHR = 1.73) and CVD mortality by 93% (aHR = 1.93). In the highest versus lowest quartiles, RDW (aHR = 1.89) and RAR (aHR = 2.91) were associated with higher all-cause mortality risk, and even higher risk for CVD mortality (RDW: aHR = 2.86; RAR: aHR = 4.84). The AUC for 5-year predictions was RDW 0.825 and RAR 0.846 for all-cause mortality, and RDW 0.811 and RAR 0.814 for CVD mortality.
Conclusions
RDW and RAR are strong predictors of long-term mortality in individuals with DN. RAR demonstrates stronger associations and higher predictive accuracy than RDW, particularly in predicting CVD mortality.
{"title":"Red cell distribution width (RDW), RDW to albumin ratio (RAR), and long-term mortality in diabetic neuropathy: A NHANES analysis, 1999–2019","authors":"Jui-Chu Huang, Pey-Jium Chang, Yi-Lun Chiang","doi":"10.1111/jdi.70147","DOIUrl":"10.1111/jdi.70147","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>We aimed to explore associations between Red cell distribution width (RDW), RDW to albumin ratio (RAR), and long-term all-cause and cardiovascular disease (CVD) mortality in adults with diabetes and DN.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study included adults aged ≥40 years with DN from the National Health and Nutrition Examination Survey from 1999 to 2004, followed through 2019. Cox proportional hazards models were used to assess associations between RDW, RAR, and all-cause and CVD mortality. Predictive accuracy was determined using area under the curve (AUC) by receiver operating characteristic analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Data of a total of 624 participants with DN were analyzed. Each unit increase in RDW significantly increased all-cause mortality by 12% (adjusted hazard ratio (aHR) = 1.12, 95% CI: 1.05–1.20) and CVD mortality by 15% (aHR = 1.15, 95% CI: 1.02–1.31), while each unit increase in RAR increased all-cause mortality by 73% (aHR = 1.73) and CVD mortality by 93% (aHR = 1.93). In the highest versus lowest quartiles, RDW (aHR = 1.89) and RAR (aHR = 2.91) were associated with higher all-cause mortality risk, and even higher risk for CVD mortality (RDW: aHR = 2.86; RAR: aHR = 4.84). The AUC for 5-year predictions was RDW 0.825 and RAR 0.846 for all-cause mortality, and RDW 0.811 and RAR 0.814 for CVD mortality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>RDW and RAR are strong predictors of long-term mortality in individuals with DN. RAR demonstrates stronger associations and higher predictive accuracy than RDW, particularly in predicting CVD mortality.</p>\u0000 </section>\u0000 </div>","PeriodicalId":51250,"journal":{"name":"Journal of Diabetes Investigation","volume":"16 11","pages":"2040-2047"},"PeriodicalIF":3.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jdi.70147","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study was to ascertain the clinical performance of OIP5-AS1 in diabetic retinopathy (DR) and its molecular mechanism in the disease progression.
Materials and Methods
Subjects included 85 healthy controls, 79 patients with type 2 diabetes mellitus (T2DM), and 114 T2DM-DR patients. qRT-PCR was conducted to measure the relative abundances of OIP5-AS1 and miR-181a-5p in the research subjects. Receiver operating characteristic (ROC) and logistic regression analyses were employed for the diagnostic capability and risk factor prediction. Cell activities were assessed using CCK-8 and transwell assays. Luciferase reporter assay was used for the correlation confirmation of OIP5-AS1 and miR-181a-5p. Bioinformatic analysis was applied to predict the potential targets of miR-181a-5p.
Results
A significant decrease of OIP5-AS1 was detected in serum from patients with T2MD and T2DM-DR (P < 0.001), exhibiting a high diagnostic value for detecting T2DM (AUC = 0.973) and T2DM-DR patients (AUC = 0.913). OIP5-AS1 was an independent protective indicator for the onset of T2DM-proliferative DR (T2DM-PDR; P = 0.021, OR = 0.306, 95%CI = 0.112–0.837). OIP5-AS1 was markedly reduced in human retinal vascular endothelial cells (HRVECs) with high glucose (HG) (P < 0.001). Overexpression of OIP5-AS1 could significantly suppress the cell growth of HRVECs (P < 0.001). OIP5-AS1 was negatively correlated with miR-181a-5p (r = −0.5327, P < 0.001). Additionally, the impacts caused by OIP5-AS1 on cell events were canceled by transfection of miR-181a-5p mimic (P < 0.001). The possible targets of miR-181a-5p were mined, suggesting mainly enriched in cellular senescence and the MAPK signaling pathway.
Conclusions
OIP5-AS1 was downregulated in T2DM-DR patients and regulated cellular functions via targeting miR-181a-5p. It might offer a new therapeutic target for the disease.
{"title":"Dysregulation of lncRNA OIP5-AS1 participants in the progression of diabetic retinopathy and affects the proliferation in retinal vascular endothelial cell","authors":"Ziwen Yin, Jingyun Dong, Yachao Meng, Zhiqiang Yang, Chunhong Zhao, Qiuyun Wu","doi":"10.1111/jdi.70091","DOIUrl":"10.1111/jdi.70091","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>This study was to ascertain the clinical performance of OIP5-AS1 in diabetic retinopathy (DR) and its molecular mechanism in the disease progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and Methods</h3>\u0000 \u0000 <p>Subjects included 85 healthy controls, 79 patients with type 2 diabetes mellitus (T2DM), and 114 T2DM-DR patients. qRT-PCR was conducted to measure the relative abundances of OIP5-AS1 and miR-181a-5p in the research subjects. Receiver operating characteristic (ROC) and logistic regression analyses were employed for the diagnostic capability and risk factor prediction. Cell activities were assessed using CCK-8 and transwell assays. Luciferase reporter assay was used for the correlation confirmation of OIP5-AS1 and miR-181a-5p. Bioinformatic analysis was applied to predict the potential targets of miR-181a-5p.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A significant decrease of OIP5-AS1 was detected in serum from patients with T2MD and T2DM-DR (<i>P</i> < 0.001), exhibiting a high diagnostic value for detecting T2DM (AUC = 0.973) and T2DM-DR patients (AUC = 0.913). OIP5-AS1 was an independent protective indicator for the onset of T2DM-proliferative DR (T2DM-PDR; <i>P</i> = 0.021, OR = 0.306, 95%CI = 0.112–0.837). OIP5-AS1 was markedly reduced in human retinal vascular endothelial cells (HRVECs) with high glucose (HG) (<i>P</i> < 0.001). Overexpression of OIP5-AS1 could significantly suppress the cell growth of HRVECs (<i>P</i> < 0.001). OIP5-AS1 was negatively correlated with miR-181a-5p (<i>r</i> = −0.5327, <i>P</i> < 0.001). Additionally, the impacts caused by OIP5-AS1 on cell events were canceled by transfection of miR-181a-5p mimic (<i>P</i> < 0.001). The possible targets of miR-181a-5p were mined, suggesting mainly enriched in cellular senescence and the MAPK signaling pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>OIP5-AS1 was downregulated in T2DM-DR patients and regulated cellular functions via targeting miR-181a-5p. It might offer a new therapeutic target for the disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":51250,"journal":{"name":"Journal of Diabetes Investigation","volume":"16 11","pages":"1993-2004"},"PeriodicalIF":3.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jdi.70091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiujiu Liu, Yingjun Chen, Dapeng Wang, Zhaozhao Li
Introduction
Gestational diabetes mellitus (GDM) represents one of the most prevalent medical complications during pregnancy. Emerging evidence has implicated NOL1/NOP2/SUN domain (NSUN)2-mediated 5-methylcytosine (m5C) methylation modifications in various pathological conditions. This study aimed to investigate the role of m5C modification in GDM and to elucidate its underlying mechanisms.
Materials and Methods
The mRNA expression levels of m5C-related RNA methyltransferases were quantified using reverse transcription-quantitative polymerase chain reaction. Cellular viability and proliferation were assessed through Cell Counting Kit-8 and EdU assays. The apoptosis rate was determined by flow cytometry. Western blot was employed to analyze autophagy-related protein expression. The m5C modification sites on PTEN-induced putative kinase 1 (PINK1) were identified via dual-luciferase reporter assays. An RNA immunoprecipitation assay was performed to examine NSUN2-PINK1 interactions. Finally, a mouse model was established to further explore the role of NSUN2 in GDM in vivo.
Results
Our findings revealed elevated NSUN2 expression in HTR-8/SVneo cells. NSUN2-mediated m5C modification suppressed proliferation while enhancing apoptosis, inflammation, and autophagy in high glucose (HG)-stimulated HTR-8/SVneo cells. Mechanistically, NSUN2 upregulated PINK1 expression through an m5C-dependent regulation. Pharmacological inhibition of PINK1 reversed these effects, enhancing proliferation while attenuating apoptosis, inflammation, and autophagy under HG conditions. Conversely, PINK1 overexpression exacerbated the observed cellular responses. In vivo, NSUN2 inhibition alleviated inflammation and hyperglycemia in GDM pregnant mice.
Conclusions
NSUN2-mediated m5C modification promoted GDM progression by upregulating PINK1 expression, leading to impaired trophoblast function. Targeting this NSUN2-m5C-PINK1 axis may represent a promising therapeutic strategy for GDM management.
{"title":"NSUN2-mediated m5C methylation modification regulates trophoblast cell proliferation, apoptosis, and autophagy in gestational diabetes mellitus","authors":"Jiujiu Liu, Yingjun Chen, Dapeng Wang, Zhaozhao Li","doi":"10.1111/jdi.70140","DOIUrl":"10.1111/jdi.70140","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Gestational diabetes mellitus (GDM) represents one of the most prevalent medical complications during pregnancy. Emerging evidence has implicated NOL1/NOP2/SUN domain (NSUN)2-mediated 5-methylcytosine (m<sup>5</sup>C) methylation modifications in various pathological conditions. This study aimed to investigate the role of m<sup>5</sup>C modification in GDM and to elucidate its underlying mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and Methods</h3>\u0000 \u0000 <p>The mRNA expression levels of m<sup>5</sup>C-related RNA methyltransferases were quantified using reverse transcription-quantitative polymerase chain reaction. Cellular viability and proliferation were assessed through Cell Counting Kit-8 and EdU assays. The apoptosis rate was determined by flow cytometry. Western blot was employed to analyze autophagy-related protein expression. The m<sup>5</sup>C modification sites on PTEN-induced putative kinase 1 (PINK1) were identified via dual-luciferase reporter assays. An RNA immunoprecipitation assay was performed to examine NSUN2-PINK1 interactions. Finally, a mouse model was established to further explore the role of NSUN2 in GDM <i>in vivo</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our findings revealed elevated NSUN2 expression in HTR-8/SVneo cells. NSUN2-mediated m<sup>5</sup>C modification suppressed proliferation while enhancing apoptosis, inflammation, and autophagy in high glucose (HG)-stimulated HTR-8/SVneo cells. Mechanistically, NSUN2 upregulated PINK1 expression through an m<sup>5</sup>C-dependent regulation. Pharmacological inhibition of PINK1 reversed these effects, enhancing proliferation while attenuating apoptosis, inflammation, and autophagy under HG conditions. Conversely, PINK1 overexpression exacerbated the observed cellular responses. <i>In vivo</i>, NSUN2 inhibition alleviated inflammation and hyperglycemia in GDM pregnant mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>NSUN2-mediated m<sup>5</sup>C modification promoted GDM progression by upregulating PINK1 expression, leading to impaired trophoblast function. Targeting this NSUN2-m<sup>5</sup>C-PINK1 axis may represent a promising therapeutic strategy for GDM management.</p>\u0000 </section>\u0000 </div>","PeriodicalId":51250,"journal":{"name":"Journal of Diabetes Investigation","volume":"16 11","pages":"2005-2017"},"PeriodicalIF":3.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jdi.70140","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cofilin-2 (CFL2) belongs to the cofilin family of actin-binding proteins and plays an important role in the actin homeostasis of muscle cells. CFL2 has been confirmed to regulate diabetic retinopathy (DR) progression. However, the current research is limited and more evidence is needed to reveal its role and mechanism in the DR process.
Methods
Retinal pigment epithelial (RPE) cells (ARPE-19) were cultured in high-glucose (HG; 30 mM) conditions to mimic DR cell models. Cell proliferation and apoptosis were examined by CCK8 assay, EdU assay, flow cytometry, and caspase 3 activity detection. Cell oxidative stress, ferroptosis, and inflammation were evaluated by detecting ROS, MDA, SOD, GSH, Fe2+, TNF-α, and IL-1β levels. The mRNA and protein levels of CFL2 and special protein 1 (SP1) were tested by qRT-PCR and western blot. CFL2 and SP1 interaction was assessed by ChIP assay and dual-luciferase reporter assay.
Results
HG suppressed ARPE-19 cell proliferation, while inducing apoptosis, oxidative stress, ferroptosis, and inflammation. Silencing of CFL2 alleviated HG-induced ARPE-19 cell injury by inhibiting cell apoptosis, oxidative stress, ferroptosis, and inflammation. SP1 could bind to CFL2 promoter regions to increase its expression. SP1 knockdown relieved HG-induced ARPE-19 cell injury via decreasing CFL2 expression. Besides, SP1 knockdown inhibited the activity of the AMPK/mTOR pathway, and CFL2 overexpression could reverse this effect.
Conclusions
CFL2, activated by SP1, promoted HG-induced RPE cell injury through regulating the AMPK/mTOR pathway, which might provide a potential target for DR.
{"title":"SP1-activated CFL2 promotes high glucose-induced retinal pigment epithelial cell injury and involves the AMPK/mTOR pathway","authors":"Jinan Xiao, Jingni Yu, Mei Ren","doi":"10.1111/jdi.70144","DOIUrl":"10.1111/jdi.70144","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cofilin-2 (CFL2) belongs to the cofilin family of actin-binding proteins and plays an important role in the actin homeostasis of muscle cells. CFL2 has been confirmed to regulate diabetic retinopathy (DR) progression. However, the current research is limited and more evidence is needed to reveal its role and mechanism in the DR process.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Retinal pigment epithelial (RPE) cells (ARPE-19) were cultured in high-glucose (HG; 30 mM) conditions to mimic DR cell models. Cell proliferation and apoptosis were examined by CCK8 assay, EdU assay, flow cytometry, and caspase 3 activity detection. Cell oxidative stress, ferroptosis, and inflammation were evaluated by detecting ROS, MDA, SOD, GSH, Fe<sup>2+</sup>, TNF-α, and IL-1β levels. The mRNA and protein levels of CFL2 and special protein 1 (SP1) were tested by qRT-PCR and western blot. CFL2 and SP1 interaction was assessed by ChIP assay and dual-luciferase reporter assay.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>HG suppressed ARPE-19 cell proliferation, while inducing apoptosis, oxidative stress, ferroptosis, and inflammation. Silencing of CFL2 alleviated HG-induced ARPE-19 cell injury by inhibiting cell apoptosis, oxidative stress, ferroptosis, and inflammation. SP1 could bind to CFL2 promoter regions to increase its expression. SP1 knockdown relieved HG-induced ARPE-19 cell injury via decreasing CFL2 expression. Besides, SP1 knockdown inhibited the activity of the AMPK/mTOR pathway, and CFL2 overexpression could reverse this effect.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>CFL2, activated by SP1, promoted HG-induced RPE cell injury through regulating the AMPK/mTOR pathway, which might provide a potential target for DR.</p>\u0000 </section>\u0000 </div>","PeriodicalId":51250,"journal":{"name":"Journal of Diabetes Investigation","volume":"16 11","pages":"1983-1992"},"PeriodicalIF":3.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jdi.70144","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diabetic nephropathy (DN) is an important microvascular complication of diabetes. MicroRNAs play an important role in the development of DN.
Aims
This study aims to examine the expression and clinical significance of serum miR-21-5p in patients with type 2 diabetes mellitus (T2DM) and DN.
Methods
This study enrolled a total of 106 T2DM patients, 106 T2DM patients with DN, and 70 healthy individuals. Real-time fluorescence quantitative PCR (RT-qPCR) was used to detect the expression of miR-21-5p, and the receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of miR-21-5p in DN. Pearson correlation analysis was performed to examine the association between miR-21-5p levels and estimated glomerular filtration rate (eGFR), urinary protein excretion rate (UAER) and other clinicopathological parameters of glomerulonephritis. Furthermore, the effects of miR-21-5p on the function and inflammation of human glomerular mesangial cells (HMCs) were analyzed.
Results
Serum miR-21-5p is upregulated in DN and it can effectively distinguish DN patients from T2DM patients. Pearson correlation analysis showed a negative correlation between miR-21-5p and eGFR and a positive correlation with UAER. Finally, the knockdown of miR-21-5p reduced the levels of pro-inflammatory cytokines induced by high glucose (HG) and the proliferation of HMCs.
Conclusions
Serum miR-21-5p is upregulated in DN and it might be a diagnostic marker for DN. Furthermore, miR-21-5p may be involved in the occurrence and progression of DN by regulating cell proliferation and inflammatory responses and is expected to become a potential therapeutic target for DN.
{"title":"Dysregulation of miR-21-5p in diabetic nephropathy and its role in inflammatory response","authors":"Yujiang Zhang, Qin Deng, Jianping Yi","doi":"10.1111/jdi.70098","DOIUrl":"10.1111/jdi.70098","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Diabetic nephropathy (DN) is an important microvascular complication of diabetes. MicroRNAs play an important role in the development of DN.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>This study aims to examine the expression and clinical significance of serum miR-21-5p in patients with type 2 diabetes mellitus (T2DM) and DN.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study enrolled a total of 106 T2DM patients, 106 T2DM patients with DN, and 70 healthy individuals. Real-time fluorescence quantitative PCR (RT-qPCR) was used to detect the expression of miR-21-5p, and the receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of miR-21-5p in DN. Pearson correlation analysis was performed to examine the association between miR-21-5p levels and estimated glomerular filtration rate (eGFR), urinary protein excretion rate (UAER) and other clinicopathological parameters of glomerulonephritis. Furthermore, the effects of miR-21-5p on the function and inflammation of human glomerular mesangial cells (HMCs) were analyzed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Serum miR-21-5p is upregulated in DN and it can effectively distinguish DN patients from T2DM patients. Pearson correlation analysis showed a negative correlation between miR-21-5p and eGFR and a positive correlation with UAER. Finally, the knockdown of miR-21-5p reduced the levels of pro-inflammatory cytokines induced by high glucose (HG) and the proliferation of HMCs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Serum miR-21-5p is upregulated in DN and it might be a diagnostic marker for DN. Furthermore, miR-21-5p may be involved in the occurrence and progression of DN by regulating cell proliferation and inflammatory responses and is expected to become a potential therapeutic target for DN.</p>\u0000 </section>\u0000 </div>","PeriodicalId":51250,"journal":{"name":"Journal of Diabetes Investigation","volume":"16 11","pages":"2033-2039"},"PeriodicalIF":3.0,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jdi.70098","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Dear Editor,</p><p>We read the article “Construction and validation of nomogram prediction model for ketoacidosis in elderly diabetic patients based on baseline data and glycolipid metabolism”<span><sup>1</sup></span> with great interest. This study addresses the critical need for early DKA risk identification in aging populations and leverages a multifactorial approach, which represents a valuable contribution to the field. However, significant methodological limitations threaten the validity and clinical applicability of the proposed model, necessitating clarification.</p><p>The construction of a prediction model must adhere to the events per variable (EPV) principle, typically requiring at least 10–20 outcome events (here, DKA events) per predictor variable to ensure model stability<span><sup>2</sup></span>. The training set contained only 21 DKA events, yet incorporated 8 predictor variables (age, course of disease, FBG, 2hPG, HbA1c, TG, TC, and C-peptide level), resulting in an extremely low EPV of 2.6 (21/8), far below the minimum standard of 10. In the multifactor logistic regression, SGLT2i usage (univariate analysis <i>P</i> = 0.026, OR = 4.9) was excluded due to <i>P</i> = 0.073, while C-peptide level (univariate <i>P</i> = 0.013) was retained, indicating unstable variable selection results under small sample conditions (table 2 vs. table 3). The verification set contained only nine DKA events, making it impossible to reliably evaluate a complex model with eight parameters (figure 3 verification set AUC = 0.879 with an extremely wide 95%CI: 0.670–1.000). The model is highly likely overfitted to noise in the training set, and the so-called “high predictive performance” (C-index = 0.880) is illusory. Direct clinical application would lead to misclassification of high-risk patients (e.g., neglecting the role of SGLT2i) and would likely fail during external validation.</p><p>A prediction model must demonstrate its superiority over existing strategies (e.g., intervene-all or intervene-none) through clinical utility analysis, such as decision curve analysis (DCA), and its risk stratification must cover actual clinical decision thresholds. The DCA (figure 4) only shows that “the model is superior to intervene-all/intervene-none” but does not compare it to current clinical standards (e.g., blood glucose/ketone body thresholds from ADA guidelines). The maximum total score in the model corresponds to a DKA probability of only ≈40% (figure 1), whereas clinically, true high-risk individuals needing identification (e.g., >50% risk) fall outside the model's prediction range<span><sup>3</sup></span>. The calibration curve (figure 2a,b) shows no data points in the high-risk region (predicted probability >0.4), indicating the model is used to predict high-risk patients without prior validation. The authors claim the model's value for identifying “high-risk populations” (Discussion paragraph 7), but provide no data on clinical intervention benef
{"title":"Critical methodological concerns regarding the nomogram prediction model for DKA in elderly diabetic patients","authors":"Xiaoyan Zhang, Yingxia Jiang","doi":"10.1111/jdi.70145","DOIUrl":"10.1111/jdi.70145","url":null,"abstract":"<p>Dear Editor,</p><p>We read the article “Construction and validation of nomogram prediction model for ketoacidosis in elderly diabetic patients based on baseline data and glycolipid metabolism”<span><sup>1</sup></span> with great interest. This study addresses the critical need for early DKA risk identification in aging populations and leverages a multifactorial approach, which represents a valuable contribution to the field. However, significant methodological limitations threaten the validity and clinical applicability of the proposed model, necessitating clarification.</p><p>The construction of a prediction model must adhere to the events per variable (EPV) principle, typically requiring at least 10–20 outcome events (here, DKA events) per predictor variable to ensure model stability<span><sup>2</sup></span>. The training set contained only 21 DKA events, yet incorporated 8 predictor variables (age, course of disease, FBG, 2hPG, HbA1c, TG, TC, and C-peptide level), resulting in an extremely low EPV of 2.6 (21/8), far below the minimum standard of 10. In the multifactor logistic regression, SGLT2i usage (univariate analysis <i>P</i> = 0.026, OR = 4.9) was excluded due to <i>P</i> = 0.073, while C-peptide level (univariate <i>P</i> = 0.013) was retained, indicating unstable variable selection results under small sample conditions (table 2 vs. table 3). The verification set contained only nine DKA events, making it impossible to reliably evaluate a complex model with eight parameters (figure 3 verification set AUC = 0.879 with an extremely wide 95%CI: 0.670–1.000). The model is highly likely overfitted to noise in the training set, and the so-called “high predictive performance” (C-index = 0.880) is illusory. Direct clinical application would lead to misclassification of high-risk patients (e.g., neglecting the role of SGLT2i) and would likely fail during external validation.</p><p>A prediction model must demonstrate its superiority over existing strategies (e.g., intervene-all or intervene-none) through clinical utility analysis, such as decision curve analysis (DCA), and its risk stratification must cover actual clinical decision thresholds. The DCA (figure 4) only shows that “the model is superior to intervene-all/intervene-none” but does not compare it to current clinical standards (e.g., blood glucose/ketone body thresholds from ADA guidelines). The maximum total score in the model corresponds to a DKA probability of only ≈40% (figure 1), whereas clinically, true high-risk individuals needing identification (e.g., >50% risk) fall outside the model's prediction range<span><sup>3</sup></span>. The calibration curve (figure 2a,b) shows no data points in the high-risk region (predicted probability >0.4), indicating the model is used to predict high-risk patients without prior validation. The authors claim the model's value for identifying “high-risk populations” (Discussion paragraph 7), but provide no data on clinical intervention benef","PeriodicalId":51250,"journal":{"name":"Journal of Diabetes Investigation","volume":"16 11","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jdi.70145","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Dear Editor,</p><p>The recent article by Tsuriya <i>et al</i>. (2025) in the Journal of Diabetes Investigation offers a significant post hoc analysis of the RECAP study, addressing a crucial gap in the understanding of the hepatoprotective effects of combination therapy with sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) in patients with type 2 diabetes. This study underscores its clinical relevance by incorporating data from 643 patients across 18 centers, thereby reflecting a wide range of clinical practices<span><sup>1</sup></span>. The longitudinal design, with a mean follow-up period of 61.8 months, evaluates liver function dynamics using the fibrosis-4 (FIB-4) index and aminotransferase levels at three distinct time points: baseline, initiation of combination therapy, and final observation. The findings indicate significant reductions in aspartate aminotranstransferase (AST) and alanine aminotranstransferase (ALT) levels following the initiation of combination therapy. The methodological strengths of this study include the use of rigorous propensity score matching to mitigate confounding variables, analysis of treatment sequences (comparing SGLT2 inhibitors and GLP-1 receptor agonists in preceding groups), and innovative subgroup analyses stratified by FIB-4 categories and ALT thresholds (≥30 IU/L) to identify responsive subpopulations, thereby reinforcing personalized treatment approaches. The conclusion—that combination therapy enhances liver function and reduces fibrosis progression in high-risk patients (with a baseline FIB-4 score of ≥1.3)—is consistent with emerging evidence regarding the pleiotropic benefits of these agents. This conclusion is further supported by statistical rigor achieved through multiple imputation for missing data and the application of Rubin's rule for pooled estimates. However, despite these strengths, several limitations necessitate cautious interpretation of the findings:</p><p>The study predominantly utilizes surrogate markers, namely fibrosis-4 (FIB-4), Hepatic Steatosis Index (HSI), and alanine aminotranstransferase (ALT), without integrating established diagnostic criteria for metabolic-associated steatotic liver disease (MASLD). Although the fibrosis-4 (FIB-4) index is practical, its reliability is compromised in individuals under 35 years of age or those experiencing acute inflammation, due to its significant age dependency. Notably, the study does not report critical confounding variables such as abdominal obesity, triglyceride levels, high-density lipoprotein cholesterol (HDL-C), and insulin resistance. This omission is particularly consequential, given the pivotal role of metabolic dysregulation in the progression of MASLD<span><sup>2</sup></span>. In the absence of these data, the observed “hepatoprotective” effects may be misattributed, potentially conflating metabolic improvements with the direct effects of the drug under investigation
{"title":"Commentary on “Liver function effects of SGLT2 inhibitor and GLP-1 receptor agonist combination treatment in patients with type 2 diabetes (post hoc analysis of RECAP study)”","authors":"Yu Zhang, Yiyan Han, Qu Zheng, Xingxing Lin","doi":"10.1111/jdi.70143","DOIUrl":"10.1111/jdi.70143","url":null,"abstract":"<p>Dear Editor,</p><p>The recent article by Tsuriya <i>et al</i>. (2025) in the Journal of Diabetes Investigation offers a significant post hoc analysis of the RECAP study, addressing a crucial gap in the understanding of the hepatoprotective effects of combination therapy with sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) in patients with type 2 diabetes. This study underscores its clinical relevance by incorporating data from 643 patients across 18 centers, thereby reflecting a wide range of clinical practices<span><sup>1</sup></span>. The longitudinal design, with a mean follow-up period of 61.8 months, evaluates liver function dynamics using the fibrosis-4 (FIB-4) index and aminotransferase levels at three distinct time points: baseline, initiation of combination therapy, and final observation. The findings indicate significant reductions in aspartate aminotranstransferase (AST) and alanine aminotranstransferase (ALT) levels following the initiation of combination therapy. The methodological strengths of this study include the use of rigorous propensity score matching to mitigate confounding variables, analysis of treatment sequences (comparing SGLT2 inhibitors and GLP-1 receptor agonists in preceding groups), and innovative subgroup analyses stratified by FIB-4 categories and ALT thresholds (≥30 IU/L) to identify responsive subpopulations, thereby reinforcing personalized treatment approaches. The conclusion—that combination therapy enhances liver function and reduces fibrosis progression in high-risk patients (with a baseline FIB-4 score of ≥1.3)—is consistent with emerging evidence regarding the pleiotropic benefits of these agents. This conclusion is further supported by statistical rigor achieved through multiple imputation for missing data and the application of Rubin's rule for pooled estimates. However, despite these strengths, several limitations necessitate cautious interpretation of the findings:</p><p>The study predominantly utilizes surrogate markers, namely fibrosis-4 (FIB-4), Hepatic Steatosis Index (HSI), and alanine aminotranstransferase (ALT), without integrating established diagnostic criteria for metabolic-associated steatotic liver disease (MASLD). Although the fibrosis-4 (FIB-4) index is practical, its reliability is compromised in individuals under 35 years of age or those experiencing acute inflammation, due to its significant age dependency. Notably, the study does not report critical confounding variables such as abdominal obesity, triglyceride levels, high-density lipoprotein cholesterol (HDL-C), and insulin resistance. This omission is particularly consequential, given the pivotal role of metabolic dysregulation in the progression of MASLD<span><sup>2</sup></span>. In the absence of these data, the observed “hepatoprotective” effects may be misattributed, potentially conflating metabolic improvements with the direct effects of the drug under investigation","PeriodicalId":51250,"journal":{"name":"Journal of Diabetes Investigation","volume":"16 11","pages":"2120-2122"},"PeriodicalIF":3.0,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jdi.70143","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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