Diabetologia最新文献

{"title":"Perspectives on prevention of type 1 diabetes and heterogeneities.","authors":"Lars C Stene","doi":"10.1007/s00125-025-06512-5","DOIUrl":"https://doi.org/10.1007/s00125-025-06512-5","url":null,"abstract":"Preventing type 1 diabetes remains a significant challenge but ongoing efforts are bringing us closer to this goal. This article discusses some implications of heterogeneity and chance in relation to prevention of type 1 diabetes, particularly regarding interpretation of evidence and planning of future trials. Using simulations, I illustrate uncertainties in efficacy estimates in prevention trials with time-to-event endpoints, using the TN10 teplizumab trial as an example. I emphasise that risk heterogeneity does not equate to treatment effect heterogeneity. When factors modifying efficacy are taken into account, robust identification of treatment effect heterogeneity may require sample sizes approximately four times larger than those needed to determine overall efficacy in certain scenarios. Efficiency of prevention trials can be increased using 2 × 2 factorial designs investigating two treatment options. I also simulate statistical power in exploratory studies involving multiple testing with different strategies for handling potential type 1 diabetes endotypes. If endotypes are defined as subtypes of type 1 diabetes-related phenotypes with at least partially unique risk factors, it becomes clear that we should aim to discover actionable aetiological factors that are not endotype-specific. Subjective judgements and pragmatism will influence whether and how a prevention trial is planned. Current approaches target high-risk individuals, which reduces the required number of trial participants but increases the cost of identifying trial participants. A prevention trial targeting infants in the general population with a multivalent antiviral vaccine will likely need over 50,000 participants, depending on circumstances and assumptions. While such a trial is conceivable, it would demand robust safety data before initiation.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"102 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of the beta cell in type 2 diabetes: new findings from the last 5 years.","authors":"Belinda Yau,Julien Ghislain,Melkam A Kebede,Jing Hughes,Vincent Poitout","doi":"10.1007/s00125-025-06499-z","DOIUrl":"https://doi.org/10.1007/s00125-025-06499-z","url":null,"abstract":"Recent advances in genome-wide approaches, the availability of isolated human islets for research and the evaluation of novel incretin mimetics in large clinical trials have brought about remarkable progress in our understanding of the role of the pancreatic beta cell in type 2 diabetes. Here, we review key developments in type 2 diabetes initiation, progression and remission, focusing mostly on human studies published in the last 5 years. Progress in multi-omics technologies has enabled researchers to identify links between type 2 diabetes risk variants and gene regulatory networks in islet endocrine cells that control beta cell development, function and stress resilience. These studies support the notion that early abnormalities in insulin secretion, rather than a reduction in beta cell mass, play a fundamental and primary role in early type 2 diabetes pathogenesis. Contributing to these intrinsic beta cell defects are various pathogenic signals from other (endocrine and non-endocrine) islet cells, the exocrine pancreas, the gut and insulin-sensitive tissues. It has also become apparent that beta cells comprise a heterogeneous population that responds differently to stress situations and that sex-related differences in beta cell responses should not be underestimated. Finally, human clinical trials have clearly demonstrated that diabetes remission can be achieved using glucose-lowering therapies and particularly strategies focused on weight loss, including bariatric surgery and, more recently, the use of highly efficient new drugs targeting the incretin system. While progress in the last 5 years has been significant, much remains to be uncovered to bring these advances to the clinic and thereby alleviate the dramatic consequences of type 2 diabetes complications for the hundreds of millions of people who live with this disease.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"16 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin DEgludec/LIraglutide versus multiple daily insulin injections in the transition from hospital to outpatient management assessed by continuous glucose monitoring: the DELI transition trial.","authors":"Ana M Gómez-Medina,Diana C Henao-Carillo,Lina P Villamil-Castañeda,Yaline Gómez-Quesada,Oscar M Muñoz-Velandia,Carlos A Yepes,Salma N Chaim,Carlos E Pertuz-Noriega,Pablo Aschner","doi":"10.1007/s00125-025-06446-y","DOIUrl":"https://doi.org/10.1007/s00125-025-06446-y","url":null,"abstract":"AIMS/OBJECTIVEThe aim of the study was to assess the safety profile (defined as the percentage of patients with at least one hypoglycaemic event [more than 15 min with glucose levels <3.0 mmol/l as documented by continuous glucose monitoring] in the first 4 weeks of follow-up) for insulin degludec/liraglutide (IDegLira) compared with multiple daily insulin injections (MDI) during the transition from hospital to an outpatient setting.METHODSThe study was an open-label, randomised, controlled clinical trial comparing IDegLira to MDI after hospital discharge in patients with type 2 diabetes. The study evaluated the percentage of patients with at least one hypoglycaemic event, the hypoglycaemia event density, the time in range (TIR 3.8-10 mmol/l), the time below range (TBR <3.0 or <3.8 mmol/l), and other glycaemic management metrics measured by continuous glucose monitoring.RESULTSSixty-four patients were included in the analysis (32 in each group). They had a baseline HbA1c of 103 ± 11.6 mmol/mol (11.6 ± 1.7%) and age of 58 ± 12.4 years (means ± SD). The proportion of patients with at least one hypoglycaemic event (plasma glucose <3.0 mmol/l) was lower in the IDegLira group than in the MDI group (6.2% vs 31.3%; p<0.010), as was the hypoglycaemia event density (incidence rate ratio 15.2; 95% CI 6.2, 48.2; p<0.001), TBR <3.8 mmol/l (0.9% vs 2.9%; p=0.019) and TBR <3.0 mmol/l (0.6% vs 1.3%, p=0.008). The TIR 3.8-10 mmol/l was higher in the IDegLira group (80.6% vs 69.7%; p=0.008). The findings were consistent regardless of baseline HbA1c.CONCLUSIONS/INTERPRETATIONIDegLira proved to be safer and more effective than MDI for individuals with type 2 diabetes who had suboptimal glycaemic control, aiding in their transition from hospital to outpatient care.TRIAL REGISTRATIONClinicaltrials.gov NCT05767255 FUNDING: This research was funded by a grant from the Asociación Colombiana de Endocrinología, Diabetes y Metabolismo (ACE).","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"154 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperglycaemia in pregnancy: the role of ethnicity and geography in risk and outcomes.","authors":"Lili Yuen,Wesley Hannah,Matthew Hare,David Simmons","doi":"10.1007/s00125-025-06510-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06510-7","url":null,"abstract":"The global prevalence of hyperglycaemia in pregnancy (HIP) is rising alongside increases in the prevalence of obesity and diabetes. The IDF estimates that 19.7% of live births in 2024 were affected, with 79% of cases due to gestational diabetes mellitus (GDM) and 20% due to overt diabetes in pregnancy and pre-existing diabetes in pregnancy combined. HIP is linked to complications for both mother and child, including long-term health risks. Significant ethnic and geographical variations exist in the prevalence and outcomes of HIP, with women from South Asia being at the highest risk of GDM. Variations in prevalence of HIP exist both between regions (e.g. 13.8% in Africa compared with 31.8% in South-East Asia) and within individual countries. Social determinants of health, such as healthcare access and delivery, economic stability, discrimination, migration, lifestyle and other sociocultural factors, along with environmental, biological and genetic factors, contribute to these ethnic differences. Geography impacts risk through factors such as seasonality, pollution and rurality. Further variation occurs due to substantial diversity in national approaches to screening and diagnostic criteria. Ethnic disparities in GDM outcomes include variations in complications such as preeclampsia and preterm delivery. To address these disparities, a standardised and cost-effective approach to GDM screening and diagnosis that reflects the ethnic diversity in glucose profiles is recommended. Locally tailored, national prevention strategies for those with prior GDM should be introduced as a matter of urgency. Furthermore, each country should implement tailored HIP management policies and guidelines that include strategies to address the ethnic, geographical and social disparities in outcomes.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"29 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frequent longitudinal blood microsampling and proteome monitoring identify disease markers and enable timely intervention in a mouse model of type 1 diabetes.","authors":"Anirudra Parajuli,Annika Bendes,Fabian Byvald,Virginia M Stone,Emma E Ringqvist,Marta Butrym,Emmanouil Angelis,Sophie Kipper,Stefan Bauer,Niclas Roxhed,Jochen M Schwenk,Malin Flodström-Tullberg","doi":"10.1007/s00125-025-06502-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06502-7","url":null,"abstract":"AIMS/HYPOTHESISType 1 diabetes manifests after irreversible beta cell damage, highlighting the crucial need for markers of the presymptomatic phase to enable early and effective interventions. Current efforts to identify molecular markers of disease-triggering events lack resolution and convenience. Analysing frequently self-collected dried blood spots (DBS) could enable the detection of early disease-predictive markers and facilitate tailored interventions. Here, we present a novel strategy for monitoring transient molecular changes induced by environmental triggers that enable timely disease interception.METHODSWhole blood (10 μl) was sampled regularly (every 1-5 days) from adult NOD mice infected with Coxsackievirus B3 (CVB3) or treated with vehicle alone. Blood samples (5 μl) were dried on filter discs. DBS samples were analysed by proximity extension assay. Generalised additive models were used to assess linear and non-linear relationships between protein levels and the number of days post infection (p.i.). A multi-layer perceptron (MLP) classifier was developed to predict infection status. CVB3-infected SOCS-1-transgenic (tg) mice were treated with immune- or non-immune sera on days 2 and 3 p.i., followed by monitoring of diabetes development.RESULTSFrequent blood sampling and longitudinal measurement of the blood proteome revealed transient molecular changes in virus-infected animals that would have been missed with less frequent sampling. The MLP classifier predicted infection status after day 2 p.i. with over 90% accuracy. Treatment with immune sera on day 2 p.i. prevented diabetes development in all (100%) of CVB3-infected SOCS-1-tg NOD mice while five out of eight (62.5%) of the CVB3-infected controls treated with non-immune sera developed diabetes.CONCLUSIONS/INTERPRETATIONOur study demonstrates the utility of frequently collected DBS samples to monitor dynamic proteome changes induced by an environmental trigger during the presymptomatic phase of type 1 diabetes. This approach enables disease interception and can be translated into human initiatives, offering a new method for early detection and intervention in type 1 diabetes.DATA AND CODE AVAILABILITYAdditional data available at https://doi.org/10.17044/scilifelab.27368322 . Additional visualisations are presented in the Shiny app interface https://mouse-dbs-profiling.serve.scilifelab.se/ .","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"20 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What are the most important research questions within prediabetes? A priority setting partnership in collaboration with patients, healthcare professionals and researchers.","authors":"Amalie K Andersen,Kristian D Lyng,Kristine Færch,Dorte Vistisen,Bernt J von Scholten,Michael S Rathleff,Janus L Thomsen,Morten H Jensen","doi":"10.1007/s00125-025-06505-4","DOIUrl":"https://doi.org/10.1007/s00125-025-06505-4","url":null,"abstract":"AIMS/HYPOTHESISResearch agendas are typically set by researchers and funders, meaning that priorities of end users, such as patients and healthcare professionals (HCPs), could be missed or overlooked in research. To ensure future research in prediabetes is of relevance and benefit to people with prediabetes and HCPs, it is important to involve these stakeholders in setting the research agenda. The aim of this study was to establish a top-10 list of the most important research questions in prediabetes (HbA1c 42-47 mmol/mol [6.0-6.4%]) by involving and collaborating with patients, relatives, patient organisations, HCPs and researchers.METHODSWe used a modified James Lind Alliance Priority Setting Partnership methodology, following the four-step process including: (1) Gathering uncertainties; (2) Organising uncertainties; (3) Interim priority setting; and (4) Final priority setting in a workshop. Further, the international relevance of the final top-10 list was assessed.RESULTSA total of 1142 responses were submitted by 405 people to: 'What questions about prediabetes would you like to see answered by research?'. The collected uncertainties were categorised and condensed into 35 indicative questions. Through prioritisation, patients and relatives had different preferences from researchers and HCPs. The jointly agreed top-10 list included questions on prevention strategies, risk factors, diet advice, screening and personalised treatment. Highest prioritisation was given to: 'What is the best prevention of diabetes and will early prevention strategies reduce the number of people with type 2 diabetes?'.CONCLUSIONS/INTERPRETATIONAn iterative and collaborative process identified shared priorities between patients, HCPs and relevant stakeholders in prediabetes. Findings should support academia, funders and the healthcare industry to target research within prediabetes specifically to the needs of patients and HCPs.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"6 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variation in type 2 diabetes prevalence across different populations: the key drivers.","authors":"Joanna Y Gong,Seyedeh Forough Sajjadi,Ayesha A Motala,Jonathan E Shaw,Dianna J Magliano","doi":"10.1007/s00125-025-06478-4","DOIUrl":"https://doi.org/10.1007/s00125-025-06478-4","url":null,"abstract":"The global prevalence of type 2 diabetes has risen sharply in recent decades, with significant regional and demographic variation. While high- and middle-income countries generally report a higher diabetes prevalence than low-income countries, substantial differences exist within these categories. The highest prevalence is observed in regions such as the Middle East and North Africa, whereas parts of Europe and sub-Saharan Africa report a much lower prevalence. Several factors drive these disparities, including urbanisation and industrialisation, which have led to changing lifestyles, including more sedentary behaviours and greater consumption of processed, energy-dense foods, particularly in rapidly developing economies. The rising prevalence of obesity, driven by these lifestyle changes, further exacerbates health disparities, significantly increasing the risk of developing type 2 diabetes. Declining mortality rates among people with diabetes, and incidence, will also impact prevalence. Genetic predisposition influences diabetes risk, with certain populations, such as Indigenous and Pacific Islander groups, exhibiting higher susceptibility. Environmental factors, including air pollution and persistent organic pollutants, also impact diabetes prevalence, and disproportionately affect lower income regions. Migration plays a role at both individual and population levels, with migrant populations from high-risk regions often having a higher diabetes prevalence than host populations due to lifestyle and socioeconomic changes they experience. Additionally, healthcare access and diagnostic practices vary widely, leading to underdiagnosis of type 2 diabetes, particularly in low-resource settings. Addressing these disparities requires a comprehensive approach that considers socioeconomic factors, environmental factors and weight management to develop effective prevention and intervention strategies worldwide.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"13 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical utility of self-reported sleep duration and insomnia symptoms in type 2 diabetes prediction.","authors":"Alison K Wright,Tianyi Huang,Matthew J Carr,Arjun D Premdayal,Sushant Saluja,Hassan S Dashti,Simon G Anderson,David W Ray,Samuel E Jones,Andrew R Wood,Timothy M Frayling,Michael N Weedon,Jacqueline M Lane,Richa Saxena,Junxi Liu,Jack Bowden,Deborah A Lawlor,Susan Redline,Martin K Rutter","doi":"10.1007/s00125-025-06503-6","DOIUrl":"https://doi.org/10.1007/s00125-025-06503-6","url":null,"abstract":"AIMS/HYPOTHESISSuboptimal sleep health is linked to higher risks for incident type 2 diabetes. We aimed to assess the clinical utility of adding self-reported sleep traits to a type 2 diabetes prediction model.METHODSIn this cohort study, we used UK Biobank data and Cox proportional hazards models to examine how self-reported sleep duration and insomnia symptoms were associated with incident type 2 diabetes risk. Harrell's C statistic and net reclassification improvement (NRI) were used to assess whether sleep traits improved the incident type 2 diabetes discrimination and predictive utility achieved using QDiabetes variables, with and without including a type 2 diabetes polygenic risk score (PGS). Independent replication was explored in the Nurses' Health Study, the Nurses' Health Study II and the Health Professionals Follow-up Study.RESULTSExtremes of sleep duration and occasional or frequent insomnia symptoms were associated with higher risks for incident type 2 diabetes. In the UK Biobank and replication cohorts, adding sleep traits to the QDiabetes risk score did not improve type 2 diabetes prediction (C statistic: QDiabetes alone 0.8933; QDiabetes + sleep duration 0.8939; QDiabetes + insomnia 0.8931; QDiabetes + sleep traits 0.8935). The corresponding total NRI values were: 0.08 (95% CI -0.18, 0.33), 0.04 (95% CI -0.08, 0.16) and 0.04 (95% CI -0.10, 0.18). Inclusion of PGS data marginally improved the type 2 diabetes risk prediction achieved using The QDiabetes calculator, with or without the inclusion of sleep traits in the model (QDiabetes + PGS: C statistic 0.8945; total NRI 0.20 [95% CI 0.12, 0.28]; QDiabetes + PGS + sleep traits: C statistic 0.8946; total NRI 0.18 [95% CI 0.09, 0.27]).CONCLUSIONS/INTERPRETATIONWhile sleep duration and insomnia symptoms were associated with type 2 diabetes risk, they are not useful for improving type 2 diabetes prediction beyond QDiabetes model performance. Inclusion of a type 2 diabetes PGS marginally improved prediction but lacked clear clinical utility.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"12 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144766076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune cell-adipose tissue crosstalk in metabolic diseases with a focus on type 1 diabetes.","authors":"Fawaz Alzaid, Guy Fagherazzi, Jean-Pierre Riveline, Fatemah Bahman, Fatema Al-Rashed, Fahd Al-Mulla, Rasheed Ahmad","doi":"10.1007/s00125-025-06437-z","DOIUrl":"10.1007/s00125-025-06437-z","url":null,"abstract":"<p><p>Adipose tissue, once regarded merely as an energy reservoir, has emerged as a critical regulator of both metabolic and immune processes. This paradigm shift has profound implications for understanding and managing type 1 diabetes, a condition typically associated with lean individuals. The growing global prevalence of obesity has introduced an underexplored dimension to type 1 diabetes pathophysiology, a phenomenon that has significant consequences for disease development, progression and management. The coexistence of obesity and type 1 diabetes presents unique challenges, including exacerbation of insulin resistance and an elevated risk of complications such as CVD. Obesity-induced chronic low-grade inflammation, or 'meta-inflammation', creates a proinflammatory environment within adipose tissue. This disrupts systemic immune regulation, promotes insulin resistance and may even potentiate autoimmunity directed to pancreatic beta cells. Addressing these interactions will allow us to reframe research priorities and the management of type 1 diabetes in individuals who also live with obesity. In this review, we explore how adipose tissue maladaptation in obesity influences the pathophysiology of type 1 diabetes. We discuss existing literature and gaps in knowledge, and emphasise the importance of addressing these gaps. We also highlight the potential of emerging technologies and precision medicine to tackle the dual challenge of obesity and type 1 diabetes. Advances such as continuous glucose monitoring and automated insulin delivery systems and insights from genomics and metabolomics are revolutionising diabetes care. These tools can enhance glucose management and provide opportunities to mitigate weight-related complications and personalise treatment strategies.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1616-1631"},"PeriodicalIF":8.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12246022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METRNL represses beta-to-alpha cell trans-differentiation to maintain beta cell function under diabetic metabolic stress in mice.","authors":"Yuxia Zhou, Laying Hu, Ruijuan Zhuang, Lingyu Song, Xuebing Chang, Lu Liu, Yali Huang, Miao Zhang, Jing Zheng, Xiaohui Xu, Tuanlao Wang, Bing Guo","doi":"10.1007/s00125-025-06459-7","DOIUrl":"10.1007/s00125-025-06459-7","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>In type 2 diabetes mellitus, beta cell failure is associated with pancreatic beta cell dedifferentiation and trans-differentiation into other types of islet cells. However, the mechanisms underlying this process remain unclear. Recently, meteorin-like (METRNL) protein, a newly discovered secretory protein, has demonstrated beneficial effects in obesity and insulin resistance. However, its role in islet cell function, particularly in differentiated beta cells, remains to be elucidated. This study aims to investigate the effects of Metrnl gene deletion in beta cells on islet function and determine whether METRNL-mediated maintenance of islet cell identity is necessary for beta cell compensation in diabetes.</p><p><strong>Methods: </strong>Mice with a specific deletion of Metrnl in beta cells were studied under both normal (chow diet) and metabolic stress (high-fat diet [HFD]) conditions. The investigation focused on their glucose tolerance, insulin secretion, islet gene expression and glucose-stimulated insulin secretion (GSIS). Additionally, cell developmental trajectory and cell-cell interaction analyses of the isolated islets were conducted using single-cell RNA-seq. Furthermore, the impact of METRNL replenishment on the regulation of beta cells in response to HFD feeding or in db/db mice was also examined.</p><p><strong>Results: </strong>METRNL was predominantly expressed in islet beta cells. However, its expression was reduced in the islets of db/db or HFD/streptozocin-induced mice, which positively correlated with insulin expression in these diabetic mice. Furthermore, the deletion of Metrnl in beta cells disrupted insulin secretion in mice fed with HFD, resulting in worsened diabetes and glucose intolerance. Pancreatic islets isolated from METRNL-deficient mice also exhibited reduced insulin secretion in GSIS assays in vitro. Additionally, single-cell RNA-seq analysis of isolated islets demonstrated that METRNL deficiency in beta cells was associated with a potential evolutionary differentiation relationship, indicating a trajectory toward alpha cells. This beta-to-alpha cell trans-differentiation was further evidenced by the upregulation of alpha cell genes (e.g. Gcg, Arx and Irx2) and downregulation of beta cell identity genes (e.g. Ins1, Ins2, Pdx1, and Mafa). Furthermore, METRNL deficiency was found to promote beta-to-alpha cell trans-differentiation during metabolic stress by impairing beta cell capacity, partially due to increased c-Jun levels. On the other hand, as a crucial executor of Kruppel-like transcription factor 6 (KLF6), METRNL may play an important role in maintaining beta cell integrity and function under metabolic stress. Moreover, recombinant METRNL administration significantly improved glucose uptake, lessened the severity of insulin resistance and increased plasma insulin levels in both HFD-fed and db/db mice.</p><p><strong>Conclusions/interpretation: </strong>METRNL helps to maintai","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1769-1788"},"PeriodicalIF":8.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}