Diabetologia最新文献

{"title":"Immunotherapy with low-dose IL-2 attenuates vascular injury in mice with diabetic and neovascular retinopathy by restoring the balance between Foxp3+ Tregs and CD8+ T cells","authors":"Devy Deliyanti, Varaporn Suphapimol, Amit Joglekar, Abhirup Jayasimhan, Jennifer L. Wilkinson-Berka","doi":"10.1007/s00125-025-06412-8","DOIUrl":"https://doi.org/10.1007/s00125-025-06412-8","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Diabetic retinopathy features damage to the retinal microvasculature that causes vessels to leak and proliferate and can lead to vision loss and blindness. Inflammation contributes to the development of diabetic retinopathy, but little is known about the role of the adaptive immune system, including the benefits of augmenting the Forkhead box protein P3 (Foxp3) regulatory T cell (Treg) compartment. We aimed to determine whether treatment with low-dose IL-2 expands and activates Tregs and reduces CD8<sup>+</sup> T cells in the retina, and attenuates retinal inflammation and vasculopathy in murine models of diabetic retinopathy and neovascular retinopathy.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Mouse models of streptozocin-induced diabetes and oxygen-induced retinopathy (OIR) were administered low-dose IL-2 (25,000 U) or vehicle (sterile water) by i.p. injection. Reporter mice expressing Foxp3 as a red fluorescent protein (RFP) conjugate or CD8 as a green fluorescent protein (GFP) conjugate were used to evaluate Foxp3<sup>+</sup> Tregs and CD8<sup>+</sup> T cells, respectively, in blood, lymphoid organs and retina using flow cytometry or confocal microscopy. Vasculopathy and the expression of angiogenic and inflammatory factors were assessed in the retina.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Low-dose IL-2 significantly expanded CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup> Tregs in the blood and spleen of mouse models of OIR and diabetes (1.4- to 1.9-fold increase, <i>p</i><0.01). This expansion enhanced Treg functionality, increasing the expression of cytotoxic T-lymphocyte-associated protein4 (CTLA4), programmed cell death protein1 (PD1) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), and increased the ratio of Tregs to CD8<sup>+</sup> T cells. This was accompanied in the retina by a twofold increase in Foxp3<sup>+</sup> Tregs (diabetes: 3.01 ± 0.41 vs 5.90 ± 1.25 cells per field, <i>p</i><0.001; OIR: 4.41 ± 1.48 vs 10.05 ± 2.91 cells per field, <i>p</i><0.001) and a reduction in CD8<sup>+</sup> T cells (diabetes: 4.65 ± 0.58 vs 3.00 ± 0.81 cells per field, <i>p</i><0.01; OIR: 5.51 ± 1.33 vs 3.17 ± 1.14 cells per field, <i>p</i><0.01). Low-dose IL-2 reduced the levels of the potent inflammatory factors intercellular adhesion protein1 and TNF and the chemokine IFNγ-inducible protein10 (IP-10) in the retina. Importantly, low-dose IL-2 treatment effectively attenuated retinal vasculopathy, with marked reductions in acellular capillaries (diabetes: 0.48-fold decrease, <i>p</i><0.001), neovascularisation (OIR: 0.68-fold decrease, <i>p</i><0.01) and vascular leakage, and expression of vascular endothelial growth factor.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>This study highlights the therapeutic potential of low-dose IL-2 to reduc","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"33 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703045","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":"Quinine: rediscovery of an old glucose-lowering drug.","authors":"Jean-Claude Henquin","doi":"10.1007/s00125-025-06416-4","DOIUrl":"https://doi.org/10.1007/s00125-025-06416-4","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708988","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":"Early weight loss, diabetes remission and long-term trajectory after diagnosis of type 2 diabetes: a retrospective study","authors":"Mario Luca Morieri, Mauro Rigato, Vera Frison, Michele D’Ambrosio, Giovanni Sartore, Angelo Avogaro, Gian Paolo Fadini","doi":"10.1007/s00125-025-06402-w","DOIUrl":"https://doi.org/10.1007/s00125-025-06402-w","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Weight loss can improve glycaemic management in individuals with type 2 diabetes, but its long-term effects on remission, cardiovascular risk factors and complications remain unclear. We investigated clinical outcomes following non-interventional ≥10% body weight loss in people with newly diagnosed type 2 diabetes in a routine care setting.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We retrospectively analysed two cohorts of people with newly diagnosed type 2 diabetes. After exclusions, cohort 1 included 1934 individuals followed for up to 25 years; cohort 2 comprised 13,277 individuals followed for up to 10 years. Participants were categorised into two groups based on whether or not they lost at least 10% body weight. In a sensitivity analysis, a group of participants with intermediate weight loss (5% to &lt;10%) was also considered. Outcomes included HbA_1c, diabetes remission, cardiovascular parameters and chronic complications.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Participants (58% male) had a mean age of 62 years and a mean diabetes duration of &lt;2 years at inclusion; mean baseline HbA_1c was 57–64 mmol/mol (7.4–8.0%) and mean BMI was ~30 kg/m². Weight loss ≥10% was obtained in 15.9% (<i>n</i>=308) of participants in cohort 1 and in 8.8% (<i>n</i>=1167) in cohort 2. In cohort 1, weight loss ≥10% was associated with a sustained reduction in HbA_1c (mean difference 2.1 mmol/mol; 0.19%) and a higher remission rate than in the &lt;10% weight loss group (20.2% vs 5.5%; HR 4.2). These findings were confirmed in cohort 2, with remission rates of 13.2% and 4.1% (HR 2.6) in the ≥10% and &lt;10% weight loss groups, respectively. Weight loss ≥10% improved systolic BP and HDL-cholesterol and triglyceride levels. Participants with weight loss of 5% to &lt;10% (28.2% in cohort 1 and 17.4% in cohort 2) had marginal improvements in HbA_1c, lipids and remission rates compared with participants with weight loss &lt;5%, and such results were inferior to those achieved with weight loss ≥10%. In cohort 1, compared with weight loss &lt;5% (reference), the HR for remission was 5.2 with weight loss ≥10% vs 1.7 with weight loss 5% to &lt;10%. Weight loss ≥10% was not associated with a reduced incidence of complications. On the other hand, remission was independently associated with a significantly lower rate of new-onset microangiopathy (adjusted HR 0.84; 95% CI 0.73, 0.97; <i>p</i>=0.019).</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Early weight loss of ≥10% in type 2 diabetes was associated with sustained glycaemic improvements, increasing by three to four times the rates of diabetes remission. Remission, in turn, more than weight loss was associated with a reduced risk of complications.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"22 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672743","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":"Up Front","authors":"","doi":"10.1007/s00125-025-06410-w","DOIUrl":"https://doi.org/10.1007/s00125-025-06410-w","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"3 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666070","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 efficacy of islet autoantibody screening with or without genetic pre-screening strategies for the identification of presymptomatic type 1 diabetes","authors":"Ezio Bonifacio, Raquel Coelho, Domenik A. Ewald, Gita Gemulla, Michael Hubmann, Przemyslawa Jarosz-Chobot, Mirjam Kohls, Olga Kordonouri, Vito Lampasona, Parth Narendran, Flemming Pociot, Zdenek Šumník, Agnieszka Szypowska, Jose Zapardiel-Gonzalo, Anette-Gabriele Ziegler","doi":"10.1007/s00125-025-06408-4","DOIUrl":"https://doi.org/10.1007/s00125-025-06408-4","url":null,"abstract":"<p>Early detection of type 1 diabetes, in its presymptomatic stage, offers significant clinical advantages, including treatment that can delay disease onset. Current screening focuses on identifying islet autoantibody positivity, with proposed optimal testing at ages 2, 6 and 10 years potentially achieving up to 80% sensitivity. However, challenges arise from participation rates and costs associated with multiple screenings. Genetic pre-screening has been suggested as a complementary strategy to target high-risk individuals prior to autoantibody testing, but its real-world benefits remain uncertain. Broad genetic selection strategies, based on family history, HLA typing or polygenic risk scores, can identify subsets of the population at elevated risk. However, these approaches face issues like low recall rates, socioeconomic biases and limited applicability across diverse ancestries. Additionally, the cost-effectiveness and infrastructure requirements of integrating genetic testing into routine healthcare remain significant hurdles. The combined use of genetic and autoantibody testing could improve predictive value, especially with innovations like point-of-care genetic testing. Yet, the ultimate success of any screening programme depends less on specific strategies and more on maximising public and healthcare-provider engagement, ensuring high participation, and addressing socioeconomic and demographic disparities. Digital-health infrastructure may play a crucial role in improving recall rates and maintaining follow-up adherence. In conclusion, while repeated islet autoantibody screening remains the most effective standalone approach, conducting genetic screening prior to islet autoantibody testing may be practical in certain contexts, provided that sufficient resources and equitable strategies are employed. Public engagement and robust infrastructure are essential to realising the full potential of early type 1 diabetes detection programmes.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"24 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653453","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":"Comprehensive sequencing profile and functional analysis of IsomiRs in human pancreatic islets and beta cells","authors":"Stefano Auddino, Elena Aiello, Giuseppina E. Grieco, Daniela Fignani, Giada Licata, Marco Bruttini, Alessia Mori, Andrea F. Berteramo, Erika Pedace, Laura Nigi, Caterina Formichi, Claudiane Guay, Giuseppe Quero, Vincenzo Tondolo, Gianfranco Di Giuseppe, Laura Soldovieri, Gea Ciccarelli, Andrea Mari, Andrea Giaccari, Teresa Mezza, Agnese Po, Romano Regazzi, Francesco Dotta, Guido Sebastiani","doi":"10.1007/s00125-025-06397-4","DOIUrl":"https://doi.org/10.1007/s00125-025-06397-4","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;MiRNAs regulate gene expression, influencing beta cell function and pathways. Isoforms of miRNA (isomiRs), sequence variants of miRNAs with post-transcriptional modifications, exhibit cell-type-specific expression and functions. Despite their biological significance, a comprehensive isomiR profile in human pancreatic islets and beta cells remains unexplored. This study aims to profile isomiR expression in four beta cell sources: (1) laser capture microdissected human islets (LCM-HI); (2) collagenase-isolated human islets (CI-HI); (3) sorted beta cells; and (4) the EndoC-βH1 beta cell line, and to investigate their potential role in beta cell function.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;Small RNA-seq and/or small RNA dataset analysis was conducted on human pancreatic islets and beta cells. Data were processed using the sRNAbench bioinformatics pipeline to classify isomiRs based on sequence variations. A beta cell-specific isomiR signature was identified via cross-validation across datasets. Correlations between LCM-HI isomiR expression and in vivo clinical parameters were analysed using regression models. Functional validation of isomiR-411-5p-Ext5p(+1) was performed via overexpression in EndoC-βH1 cells and CI-HI, followed by glucose-stimulated insulin secretion (GSIS) assays and/or transcriptomic analysis.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;IsomiRs constituted 59.2 ± 1.9% (LCM-HI), 59.6 ± 2.4% (CI-HI), 42.3 ± 7.2% (sorted beta cells) and 43.8 ± 1.2% (EndoC-βH1) of total miRNA reads (data represented as mean ± SD), with 3′ end trimming (Trim3p) being the predominant modification. A beta cell-specific isomiR signature of 30 sequences was identified, with isomiR-411-5p-Ext5p(+1) showing a significant inverse correlation with basal insulin secretion (&lt;i&gt;p&lt;/i&gt;=0.0009, partial &lt;i&gt;R&lt;/i&gt;&lt;sup&gt;2&lt;/sup&gt;=0.68) and total insulin secretion (&lt;i&gt;p&lt;/i&gt;=0.005, partial &lt;i&gt;R&lt;/i&gt;&lt;sup&gt;2&lt;/sup&gt;=0.54). Overexpression of isomiR-411-5p-Ext5p(+1), but not of its canonical counterpart, importantly reduced GSIS by 51% ( ± 15.2%; mean ± SD) (&lt;i&gt;p&lt;/i&gt;=0.01) in EndoC-βH1 cells. Transcriptomic analysis performed in EndoC-βH1 cells and CI-HI identified 47 genes significantly downregulated by isomiR-411-5p-Ext5p(+1) (false discovery rate [FDR]&lt;0.05) but not by the canonical miRNA, with enriched pathways related to Golgi vesicle biogenesis (FDR=0.017) and trans-Golgi vesicle budding (FDR=0.018). TargetScan analysis confirmed seed sequence-dependent target specificity for 81 genes uniquely regulated by the isomiR (&lt;i&gt;p&lt;/i&gt;=1.1 × 10⁻⁹).&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;This study provides the first comprehensive isomiR profiling in human islets and beta cells, revealing their substantial contribution to miRNA regulation. IsomiR-411-5p-Ext5p(+1) emerges as a distinct key modulator of insulin secretion and granule dynamics in beta cells. These f","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"90 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653451","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":"Enterovirus VP1 protein and HLA class I hyperexpression in pancreatic islet cells of organ donors with type 1 diabetes","authors":"Teresa Rodriguez-Calvo, Jutta E. Laiho, Maarit Oikarinen, Pouria Akhbari, Christine Flaxman, Thomas Worthington, Paola Apaolaza, John S. Kaddis, Irina Kusmartseva, Sisko Tauriainen, Martha Campbell-Thompson, Mark A. Atkinson, Matthias von Herrath, Heikki Hyöty, Noel G. Morgan, Alberto Pugliese, Sarah J. Richardson","doi":"10.1007/s00125-025-06384-9","DOIUrl":"https://doi.org/10.1007/s00125-025-06384-9","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Earlier studies of pancreases from donors with type 1 diabetes demonstrated enteroviral capsid protein VP1 in beta cells. In the context of a multidisciplinary approach undertaken by the nPOD-Virus group, we assessed VP1 positivity in pancreas and other tissues (spleen, duodenum and pancreatic lymph nodes) from 188 organ donors, including donors with type 1 diabetes and donors expressing autoantibody risk markers. We also investigated whether VP1 positivity is linked to the hyperexpression of HLA class I (HLA-I) molecules in islet cells.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;Organ donor tissues were collected by the Network for Pancreatic Organ Donors with Diabetes (nPOD) from donors without diabetes (ND, &lt;i&gt;n&lt;/i&gt;=76), donors expressing a single or multiple diabetes-associated autoantibodies (AAb&lt;sup&gt;+&lt;/sup&gt;, &lt;i&gt;n&lt;/i&gt;=20; AAb&lt;sup&gt;++&lt;/sup&gt;, &lt;i&gt;n&lt;/i&gt;=9) and donors with type 1 diabetes with residual insulin-containing islets (T1D-ICIs, &lt;i&gt;n&lt;/i&gt;=41) or only insulin-deficient islets (T1D-IDIs, &lt;i&gt;n&lt;/i&gt;=42). VP1 was assessed using immunohistochemistry (IHC) and HLA-I using IHC and immunofluorescence, in two independent laboratories. We determined assay concordance across laboratories and overall occurrence of positive assays, on a case-by-case basis and between donor groups.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Islet cell VP1 positivity was detected in most T1D-ICI donors (77.5%) vs only 38.2% of ND donors (&lt;i&gt;p&lt;/i&gt;&lt;0.001). VP1 positivity was associated with HLA-I hyperexpression. Of those donors assessed for HLA-I and VP1, 73.7% had both VP1 immunopositivity and HLA-I hyperexpression (&lt;i&gt;p&lt;/i&gt;&lt;0.001 vs ND). Moreover, VP1&lt;sup&gt;+&lt;/sup&gt; cells were detected at higher frequency in donors with HLA-I hyperexpression (&lt;i&gt;p&lt;/i&gt;&lt;0.001 vs normal HLA-I). Among VP1&lt;sup&gt;+&lt;/sup&gt; donors, the proportion with HLA-I hyperexpression was significantly higher in the AAb&lt;sup&gt;++&lt;/sup&gt; and T1D-ICI groups (94.9%, &lt;i&gt;p&lt;/i&gt;&lt;0.001 vs ND); this was not restricted to individuals with recent-onset diabetes. Critically, for all donor groups combined, HLA-I hyperexpression occurred more frequently in VP1&lt;sup&gt;+&lt;/sup&gt; compared with VP1&lt;sup&gt;−&lt;/sup&gt; donors (45.8% vs 16%, &lt;i&gt;p&lt;/i&gt;&lt;0.001).&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;We report the most extensive analysis to date of VP1 and HLA-I in pancreases from donors with preclinical and diagnosed type 1 diabetes. We find an association of VP1 with residual beta cells after diagnosis and demonstrate VP1 positivity during the autoantibody-positive preclinical stage. For the first time, we show that VP1 positivity and HLA-I hyperexpression in islet cells are both present during the preclinical stage. While the study of tissues does not allow us to demonstrate causality, our data support the hypothesis that enterovirus infections may occur throughout the natural history of type 1 diabetes and may be one ","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"61 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635668","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":"Detection of enterovirus RNA in pancreas and lymphoid tissues of organ donors with type 1 diabetes","authors":"Jutta E. Laiho, Sami Oikarinen, Sofia Morfopoulou, Maarit Oikarinen, Ashlie Renner, Daniel Depledge, Matthew C. Ross, Ivan C. Gerling, Judith Breuer, Joseph F. Petrosino, Vincent Plagnol, Alberto Pugliese, Antonio Toniolo, Richard E. Lloyd, Heikki Hyöty","doi":"10.1007/s00125-025-06359-w","DOIUrl":"https://doi.org/10.1007/s00125-025-06359-w","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>The nPOD-Virus group collaboratively applied innovative technologies to detect and sequence viral RNA in pancreas and other tissues from organ donors with type 1 diabetes. These analyses involved the largest number of pancreas samples collected to date. The aim of the current work was to examine the presence of enterovirus RNA in pancreas and lymphoid tissues of organ donors with and without type 1 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We analysed pancreas, spleen, pancreatic lymph nodes and duodenum samples from the following groups: (1) donors with type 1 diabetes (<i>n</i>=71) with (<i>n</i>=35) or without (<i>n</i>=36) insulin-containing islets; (2) donors with single or double islet autoantibody positivity without diabetes (<i>n</i>=22); and (3) autoantibody-negative donors without diabetes (control donors) (<i>n</i>=74). Five research laboratories participated in this collaborative effort using approaches for unbiased discovery of RNA viruses (two RNA-Seq platforms), targeted detection of <i>Enterovirus A–D</i> species using RT-PCR, and tests for virus growth in cell culture.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Direct RNA-Seq did not detect virus signal in pancreas samples, whereas RT-PCR detected enterovirus RNA confirmed by sequencing in low amounts in pancreas samples in three of the five donor groups: donors with type 1 diabetes with insulin-containing islets, 16% (5/32) being positive; donors with single islet autoantibody positivity, 53% (8/15) being positive; and non-diabetic donors, 8% (4/49) being positive. Detection of enterovirus RNA was significantly more frequent in single islet autoantibody-positive donors compared with donors with type 1 diabetes with insulin-deficient islets (<i>p</i>&lt;0.001) and control (non-diabetic) donors (<i>p</i>=0.004). In some donors, pancreatic lymph nodes were also positive. RT-PCR detected enterovirus RNA also in the spleen of a small number of donors and virus enrichment in susceptible cell lines before RT-PCR resulted in much higher rate in spleen positivity, particularly in donors with type 1 diabetes. Interestingly, the enterovirus strains detected did not cause a typical lytic infection, possibly reflecting their persistence-prone nature.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>This was the largest coordinated effort to examine the presence of enterovirus RNA in the pancreas of organ donors with type 1 diabetes, using a multitude of assays. These findings are consistent with the notion that donors with type 1 diabetes and donors with islet autoantibodies may carry a low-grade enterovirus infection in the pancreas and lymphoid tissues.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"55 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635673","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":"Joint analysis of the nPOD-Virus Group data: the association of enterovirus with type 1 diabetes is supported by multiple markers of infection in pancreas tissue","authors":"Sarah J. Richardson, Teresa Rodriguez-Calvo, Jutta E. Laiho, John S. Kaddis, Julius O. Nyalwidhe, Irina Kusmartseva, Sofia Morfopoulou, Joseph F. Petrosino, Vincent Plagnol, Kathrin Maedler, Margaret A. Morris, Jerry L. Nadler, Mark A. Atkinson, Matthias von Herrath, Richard E. Lloyd, Heikki Hyoty, Noel G. Morgan, Alberto Pugliese","doi":"10.1007/s00125-025-06401-x","DOIUrl":"https://doi.org/10.1007/s00125-025-06401-x","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Previous pathology studies have associated enterovirus infections with type 1 diabetes by examining the enterovirus capsid protein 1 (VP1) in autopsy pancreases obtained near diabetes diagnosis. The Network for Pancreatic Organ Donors with Diabetes (nPOD) has since obtained pancreases from organ donors with type 1 diabetes (with broad age and disease duration) and donors with disease-associated autoantibodies (AAbs), the latter representing preclinical disease. Two accompanying manuscripts from the nPOD-Virus Group report primary data from a coordinated analysis of multiple enterovirus indices. We aimed to comprehensively assess the association of multiple enterovirus markers with type 1 diabetes.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;The nPOD-Virus Group examined pancreases from 197 donors, recovered between 2007 and 2019, classified into five groups: donors with type 1 diabetes, with residual insulin-containing islets (T1D-ICI group, &lt;i&gt;n&lt;/i&gt;=41) or with only insulin-deficient islets (T1D-IDI, &lt;i&gt;n&lt;/i&gt;=42); donors without diabetes who are AAb-negative (ND, &lt;i&gt;n&lt;/i&gt;=83); and rare donors without diabetes expressing a single AAb (AAb&lt;sup&gt;+&lt;/sup&gt;, &lt;i&gt;n&lt;/i&gt;=22) or multiple AAbs (AAb&lt;sup&gt;++&lt;/sup&gt;, &lt;i&gt;n&lt;/i&gt;=9). We assessed the overall association of multiple indicators of enterovirus infection, case-by-case and between donor groups, as well as assay agreement and reproducibility, using various statistical methods. We examined data from 645 assays performed across 197 nPOD donors.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Detection of enterovirus indices by independent laboratories had high reproducibility, using both enterovirus-targeted and unbiased methods. T1D-ICI donors had significantly higher (&lt;i&gt;p&lt;/i&gt;&lt;0.001) proportions of positive assay outcomes (58.4%) vs T1D-IDI (10.3%), ND (17.8%) and AAb-positive donors (AAb&lt;sup&gt;+&lt;/sup&gt; 24.6%; AAb&lt;sup&gt;++&lt;/sup&gt; 35.0%). Head-to-head comparisons revealed increased proportions of donors positive in two independent assays among T1D-ICI vs ND donors (VP1/HLA class I [HLA-I], &lt;i&gt;p&lt;/i&gt;&lt;0.0001; VP1/enterovirus-specific RT-PCR (EV-PCR), &lt;i&gt;p&lt;/i&gt;=0.076; EV-PCR/HLA-I, &lt;i&gt;p&lt;/i&gt;=0.016; proteomics/HLA-I, &lt;i&gt;p&lt;/i&gt;&lt;0.0001; VP1/proteomics, &lt;i&gt;p&lt;/i&gt;=0.06). Among 110 donors examined for three markers (VP1, EV-PCR and HLA-I), 83.3% of T1D-ICI donors were positive in two or more assays vs 0% of ND (&lt;i&gt;p&lt;/i&gt;&lt;0.001), 26.7% of AAb&lt;sup&gt;+&lt;/sup&gt; (&lt;i&gt;p&lt;/i&gt;=0.006), 28.6% of AAb&lt;sup&gt;++&lt;/sup&gt; (&lt;i&gt;p&lt;/i&gt;=0.023) and 0% of T1D-IDI (&lt;i&gt;p&lt;/i&gt;&lt;0.001) donors.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;The nPOD-Virus Group conducted, to date, the largest and most comprehensive analysis of multiple indices of pancreatic enterovirus infections in type 1 diabetes; these were more prevalent in T1D-ICI and AAb&lt;sup&gt;++&lt;/sup&gt; donors than in other groups. Their preferential detection of these indices in donors with residu","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"33 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635672","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":"Exploring the shared genetic landscape of diabetes and cardiovascular disease: findings and future implications","authors":"Hyunsuk Lee, Maria Fernandes, Jeongeun Lee, Jordi Merino, Soo Heon Kwak","doi":"10.1007/s00125-025-06403-9","DOIUrl":"https://doi.org/10.1007/s00125-025-06403-9","url":null,"abstract":"<p>Diabetes is a rapidly growing global health concern projected to affect one in eight adults by 2045, which translates to roughly 783 million people. The profound metabolic alterations often present in dysglycaemia significantly increase the risk of cardiovascular complications. While genetic susceptibility plays a crucial role in diabetes and its vascular complications, identifying genes and molecular mechanisms that influence both diseases simultaneously has proven challenging. A key reason for this challenge is the pathophysiological heterogeneity underlying these diseases, with multiple processes contributing to different forms of diabetes and specific cardiovascular complications. This molecular heterogeneity has limited the effectiveness of large-scale genome-wide association studies (GWAS) in identifying shared underlying mechanisms. Additionally, our limited knowledge of the causal genes, cell types and disease-relevant states through which GWAS signals operate has hindered the discovery of common molecular pathways. This review highlights recent advances in genetic epidemiology, including studies of causal associations that have uncovered genetic and molecular factors influencing both dysglycaemia and cardiovascular complications. We explore how disease subtyping approaches can be critical in pinpointing the unique molecular signatures underlying both diabetes and cardiovascular complications. Finally, we address critical research gaps and future opportunities to advance our understanding of both diseases and translate these discoveries into tangible benefits for patient care and population health.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"24 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627501","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}