Diabetologia最新文献

{"title":"Macular perfusion alterations in people with recent-onset diabetes and novel diabetes subtypes","authors":"Sema Kaya, Ala Khamees, Gerd Geerling, Piotr Strzalkowski, Veronika Gontscharuk, Julia Szendroedi, Karsten Müssig, Dan Ziegler, Michael Roden, Rainer Guthoff","doi":"10.1007/s00125-025-06407-5","DOIUrl":"https://doi.org/10.1007/s00125-025-06407-5","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Our aim was to detect early structural and functional changes in the macular capillaries using optical coherence tomography angiography during the course of type 1 or 2 diabetes mellitus.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>In this cross-sectional study, individuals with type 1 diabetes (<i>n</i>=143) or type 2 diabetes (<i>n</i>=197) from the German Diabetes Study (ClinicalTrials.gov registration no. NCT01055093) underwent clinical examination and cluster analysis to identify phenotype-based diabetes subtypes, using BMI, age, HbA<sub>1c</sub>, homoeostasis model estimates and islet autoantibodies. Colour fundus photography, optical coherence tomography and optical coherence tomography angiography were performed within the first year of diabetes diagnosis (baseline) and at 5 year intervals up to year 10. Age- and sex-adjusted participants served as control participants (<i>n</i>=105). Perfusion density, vessel density, presence of retinal microaneurysms in superficial, intermediate and deep capillary plexus (SCP, ICP, DCP), choriocapillaris flow deficit density (CC FD) and the foveal avascular zone (FAZ) of the macula as well as retinal layer thickness, visual acuity and contrast sensitivity were analysed.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Perfusion density and vessel density of SCP were already reduced at baseline in type 2 diabetes (expected difference compared with control participants: −0.0071, <i>p</i>=0.0276, expected difference: −0.0034, <i>p</i>=0.0184, respectively), especially in participants with severe insulin-deficient and mild obesity-related diabetes. At year 10 only perfusion density of the SCP and DCP was reduced in both type 1 and 2 diabetes (<i>p</i>=0.0365, <i>p</i>=0.0062, respectively). The FAZ was enlarged and the CC FD within the first year increased in type 1 (<i>p</i>=0.0327, <i>p</i>=0.0474, respectively) and more markedly in type 2 diabetes (<i>p</i>=0.0006, <i>p</i><0.0001). The occurrence of microaneurysms in SCP and DCP was significant at year 5 (<i>p</i>=0.0209, <i>p</i>=0.0279, respectively) and year 10 (<i>p</i>=0.0220, <i>p</i>=0.0007). Presence of microaneurysms in SCP and DCP was associated with decreases in perfusion density and vessel density in both SCP and ICP. Furthermore, microaneurysms were associated with decreased ganglion cell layer and inner plexiform layer thickness.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Type 2 diabetes already reduces macular perfusion SCP at time of clinical diagnosis, while long-standing diabetes affects both SCP and DCP. The FAZ of the SCP and the CC FD are early indicators of diabetic alterations, with more pronounced changes observed in type 2 diabetes. Microaneurysms in the macular plexus are associated with a decrease of ganglion cell layer and inner plexiform layer. Subclinical microangiopathy occurs prior to manifestation of diabetic r","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"5 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745536","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":"HEXA-FC protein therapy increases skeletal muscle glucose uptake and improves glycaemic control in mice with insulin resistance and in a mouse model of type 2 diabetes","authors":"Magdalene K. Montgomery, Sihan Lin, Chieh-Hsin Yang, Krishneel Prasad, Zhi Li Cheng, Jacqueline Bayliss, Michael G. Leeming, Nicholas A. Williamson, Kim Loh, Li Dong, Matthew J. Watt","doi":"10.1007/s00125-025-06413-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06413-7","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Type 2 diabetes is a chronic metabolic disorder characterised by insulin resistance and sustained hyperglycaemia, and is a major cause of blindness, kidney failure, heart attacks and stroke. Our team has recently identified hexosaminidase A (HEXA) as an endocrine factor secreted by the liver that regulates sphingolipid metabolism in skeletal muscle. Specifically, HEXA converts GM2 to GM3 gangliosides within cell-surface lipid rafts. Remodelling of ganglioside composition by HEXA enhances IGF1 signalling in skeletal muscle, increasing muscle glucose uptake and improving blood glucose control.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We produced a long-acting HEXA-FC fusion protein (murine HEXA and the fragment crystallisable [FC] region from IgG1) and evaluated the effects of chronic bi-weekly HEXA-FC administration (1 mg/kg body weight) on glycaemic control in C57BL/6 mice with diet-induced obesity and insulin resistance and the <i>db</i>/<i>db</i> mouse model of severe type 2 diabetes. Outcome measures included glucose and insulin tolerance, including a stable isotope-labelled GTT and assessment of tissue-specific glucose disposal, as well as proteomics analysis to define changes in skeletal muscle metabolism.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Chronic administration of a long-acting recombinant HEXA-FC fusion protein led to improvements in random blood glucose, fasting blood glucose and glucose tolerance, driven by increased glucose disposal into skeletal muscle, effects that were associated with enhancement of IGF1 signalling in muscle.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Given that skeletal muscle is a primary site of insulin resistance in individuals with type 2 diabetes, HEXA-FC protein therapy may open new avenues for therapeutic advancement in type 2 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"30 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733951","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":"TMEM55A-mediated PI5P signalling regulates alpha cell actin depolymerisation and glucagon secretion","authors":"Xiong Liu, Theodore dos Santos, Aliya F. Spigelman, Shawn Duckett, Nancy Smith, Kunimasa Suzuki, Patrick E. MacDonald","doi":"10.1007/s00125-025-06411-9","DOIUrl":"https://doi.org/10.1007/s00125-025-06411-9","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Diabetes is associated with the dysfunction of glucagon-producing pancreatic islet alpha cells, although the underlying mechanisms regulating glucagon secretion and alpha cell dysfunction remain unclear. While insulin secretion from pancreatic beta cells has long been known to be controlled partly by intracellular phospholipid signalling, very little is known about the role of phospholipids in glucagon secretion. Using patch-clamp electrophysiology and single-cell RNA sequencing, we previously found that expression of <i>PIP4P2</i> (encoding TMEM55A, a lipid phosphatase that dephosphorylates phosphatidylinositol-4,5-bisphosphate [PIP2] to phosphatidylinositol-5-phosphate [PI5P]) correlates with alpha cell function. We hypothesise that TMEM55A is involved in glucagon secretion and aim to validate the role of TMEM55A and its potential signalling molecules in alpha cell function and glucagon secretion.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Correlation analysis was generated from the data in www.humanislets.com. Human islets were isolated at the Alberta Diabetes Institute IsletCore. Electrical recordings were performed on dispersed human or mouse islets with scrambled siRNA or si-<i>PIP4P2</i> (<i>si-Pip4p2</i> for mouse) transfection. Glucagon secretion was measured using an islet perfusion system with intact mouse islets. TMEM55A activity was measured using an in vitro on-beads phosphatase assay and live-cell imaging. GTPase activity was measured using an active GTPase pull-down assay. Confocal microscopy was used to quantify F-actin intensity using primary alpha cells and alphaTC1–9 cell lines after chemical treatment.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>TMEM55A regulated alpha cell exocytosis and glucagon secretion. TMEM55A knockdown in both human and mouse alpha cells reduced exocytosis at low glucose levels and this was rescued by the direct reintroduction of PI5P. PI5P, instead of PIP2 increased the glucagon secretion using intact mouse islets. This did not occur through an effect on Ca²⁺ channel activity but through a remodelling of cortical F-actin dependent on TMEM55A lipid phosphatase activity, which occurred in response to oxidative stress. TMEM55A- and PI5P-induced F-actin remodelling depends on the inactivation of GTPase and RhoA, instead of Ras-related C3 botulinum toxin substrate 1 or CDC42.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>We reveal a novel pathway by which TMEM55A regulates alpha cell exocytosis by controlling intracellular PI5P and the F-actin network.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"61 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712732","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":"Regulating islet stress responses through CD47 activation","authors":"Atharva Kale, Mahmoud Azar, Vanessa Cheng, Harry Robertson, Sally Coulter, Paulomi M. Mehta, Sohel M. Julovi, Ellis Patrick, Kedar Ghimire, Natasha M. Rogers","doi":"10.1007/s00125-025-06409-3","DOIUrl":"https://doi.org/10.1007/s00125-025-06409-3","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Diabetes is a global health burden characterised by incremental beta cell loss. Islet transplantation is a recognised treatment for individuals with type 1 diabetes and hypoglycaemia unawareness but broader application is constrained by limited islet survival and function post-transplantation. The underlying molecular mechanisms that induce beta cell dysfunction and demise remain unclear, and therapeutic agents that protect against cellular loss and maintain insulin secretion are in demand as potential treatment options. CD47 is a cell surface protein implicated in cellular stress responses but its role in beta cell function remains relatively unexplored. We hypothesised that modulating CD47 expression would demonstrate a cytoprotective effect in beta cells.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We used primary murine islets with/without genetic deletion of CD47, as well as human islets and MIN6 cells subjected to pharmacological disruption of CD47 signalling (siRNA or blocking antibody). Metabolic stress was induced in cells by exposure to hypoxia, hyperglycaemia or thapsigargin, and markers of the unfolded protein response, cell survival and insulin secretory function were assessed. Human pancreases from individuals with and without diabetes were examined for evidence of CD47 signalling.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Expression of CD47 and its high affinity ligand thrombospondin-1 (TSP1) was robustly upregulated by exogenous stressors. Limiting CD47 signalling improved markers of senescence, apoptosis, endoplasmic reticulum stress, unfolded protein response, self-renewal and autophagy, and maintained insulin secretory responses. We also found concurrent upregulated expression of CD47 and senescence markers in the endocrine pancreas of aged donors and those with type 2 diabetes. Both CD47 and TSP1 expression were increased in pancreases of humans with type 1 diabetes, as were plasma levels of TSP1.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Our study provides key insights into the essential role of CD47 as a novel regulator of islet dysfunction, regulating cytoprotective responses to stress. CD47 may contribute to beta cell damage during the development of diabetes and failure of islet transplant function. Therefore, limiting CD47 activation may be a potential therapeutic tool in conditions where islet function is inadequate.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"29 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703046","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":"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":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;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&lt;sup&gt;+&lt;/sup&gt; T cells in the retina, and attenuates retinal inflammation and vasculopathy in murine models of diabetic retinopathy and neovascular retinopathy.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;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&lt;sup&gt;+&lt;/sup&gt; Tregs and CD8&lt;sup&gt;+&lt;/sup&gt; 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.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Low-dose IL-2 significantly expanded CD4&lt;sup&gt;+&lt;/sup&gt;CD25&lt;sup&gt;+&lt;/sup&gt;Foxp3&lt;sup&gt;+&lt;/sup&gt; Tregs in the blood and spleen of mouse models of OIR and diabetes (1.4- to 1.9-fold increase, &lt;i&gt;p&lt;/i&gt;&lt;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&lt;sup&gt;+&lt;/sup&gt; T cells. This was accompanied in the retina by a twofold increase in Foxp3&lt;sup&gt;+&lt;/sup&gt; Tregs (diabetes: 3.01 ± 0.41 vs 5.90 ± 1.25 cells per field, &lt;i&gt;p&lt;/i&gt;&lt;0.001; OIR: 4.41 ± 1.48 vs 10.05 ± 2.91 cells per field, &lt;i&gt;p&lt;/i&gt;&lt;0.001) and a reduction in CD8&lt;sup&gt;+&lt;/sup&gt; T cells (diabetes: 4.65 ± 0.58 vs 3.00 ± 0.81 cells per field, &lt;i&gt;p&lt;/i&gt;&lt;0.01; OIR: 5.51 ± 1.33 vs 3.17 ± 1.14 cells per field, &lt;i&gt;p&lt;/i&gt;&lt;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, &lt;i&gt;p&lt;/i&gt;&lt;0.001), neovascularisation (OIR: 0.68-fold decrease, &lt;i&gt;p&lt;/i&gt;&lt;0.01) and vascular leakage, and expression of vascular endothelial growth factor.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;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":"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}