Pub Date : 2025-03-22DOI: 10.1007/s00125-025-06402-w
Mario Luca Morieri, Mauro Rigato, Vera Frison, Michele D’Ambrosio, Giovanni Sartore, Angelo Avogaro, Gian Paolo Fadini
Aims/hypothesis
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.
Methods
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 <10%) was also considered. Outcomes included HbA1c, diabetes remission, cardiovascular parameters and chronic complications.
Results
Participants (58% male) had a mean age of 62 years and a mean diabetes duration of <2 years at inclusion; mean baseline HbA1c was 57–64 mmol/mol (7.4–8.0%) and mean BMI was ~30 kg/m2. Weight loss ≥10% was obtained in 15.9% (n=308) of participants in cohort 1 and in 8.8% (n=1167) in cohort 2. In cohort 1, weight loss ≥10% was associated with a sustained reduction in HbA1c (mean difference 2.1 mmol/mol; 0.19%) and a higher remission rate than in the <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 <10% weight loss groups, respectively. Weight loss ≥10% improved systolic BP and HDL-cholesterol and triglyceride levels. Participants with weight loss of 5% to <10% (28.2% in cohort 1 and 17.4% in cohort 2) had marginal improvements in HbA1c, lipids and remission rates compared with participants with weight loss <5%, and such results were inferior to those achieved with weight loss ≥10%. In cohort 1, compared with weight loss <5% (reference), the HR for remission was 5.2 with weight loss ≥10% vs 1.7 with weight loss 5% to <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; p=0.019).
Conclusions/interpretation
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.
Graphical Abstract
{"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 <10%) was also considered. Outcomes included HbA<sub>1c</sub>, 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 <2 years at inclusion; mean baseline HbA<sub>1c</sub> was 57–64 mmol/mol (7.4–8.0%) and mean BMI was ~30 kg/m<sup>2</sup>. 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<sub>1c</sub> (mean difference 2.1 mmol/mol; 0.19%) and a higher remission rate than in the <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 <10% weight loss groups, respectively. Weight loss ≥10% improved systolic BP and HDL-cholesterol and triglyceride levels. Participants with weight loss of 5% to <10% (28.2% in cohort 1 and 17.4% in cohort 2) had marginal improvements in HbA<sub>1c</sub>, lipids and remission rates compared with participants with weight loss <5%, and such results were inferior to those achieved with weight loss ≥10%. In cohort 1, compared with weight loss <5% (reference), the HR for remission was 5.2 with weight loss ≥10% vs 1.7 with weight loss 5% to <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}
Pub Date : 2025-03-19DOI: 10.1007/s00125-025-06408-4
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
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.
Graphical Abstract
{"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}
Pub Date : 2025-03-18DOI: 10.1007/s00125-025-06397-4
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
<h3 data-test="abstract-sub-heading">Aims/hypothesis</h3><p>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.</p><h3 data-test="abstract-sub-heading">Methods</h3><p>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.</p><h3 data-test="abstract-sub-heading">Results</h3><p>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 (<i>p</i>=0.0009, partial <i>R</i><sup>2</sup>=0.68) and total insulin secretion (<i>p</i>=0.005, partial <i>R</i><sup>2</sup>=0.54). Overexpression of isomiR-411-5p-Ext5p(+1), but not of its canonical counterpart, importantly reduced GSIS by 51% ( ± 15.2%; mean ± SD) (<i>p</i>=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]<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 (<i>p</i>=1.1 × 10⁻⁹).</p><h3 data-test="abstract-sub-heading">Conclusions/interpretation</h3><p>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
{"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":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>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 (<i>p</i>=0.0009, partial <i>R</i><sup>2</sup>=0.68) and total insulin secretion (<i>p</i>=0.005, partial <i>R</i><sup>2</sup>=0.54). Overexpression of isomiR-411-5p-Ext5p(+1), but not of its canonical counterpart, importantly reduced GSIS by 51% ( ± 15.2%; mean ± SD) (<i>p</i>=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]<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 (<i>p</i>=1.1 × 10⁻⁹).</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>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}
Pub Date : 2025-03-17DOI: 10.1007/s00125-025-06384-9
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
<h3 data-test="abstract-sub-heading">Aims/hypothesis</h3><p>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.</p><h3 data-test="abstract-sub-heading">Methods</h3><p>Organ donor tissues were collected by the Network for Pancreatic Organ Donors with Diabetes (nPOD) from donors without diabetes (ND, <i>n</i>=76), donors expressing a single or multiple diabetes-associated autoantibodies (AAb<sup>+</sup>, <i>n</i>=20; AAb<sup>++</sup>, <i>n</i>=9) and donors with type 1 diabetes with residual insulin-containing islets (T1D-ICIs, <i>n</i>=41) or only insulin-deficient islets (T1D-IDIs, <i>n</i>=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.</p><h3 data-test="abstract-sub-heading">Results</h3><p>Islet cell VP1 positivity was detected in most T1D-ICI donors (77.5%) vs only 38.2% of ND donors (<i>p</i><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 (<i>p</i><0.001 vs ND). Moreover, VP1<sup>+</sup> cells were detected at higher frequency in donors with HLA-I hyperexpression (<i>p</i><0.001 vs normal HLA-I). Among VP1<sup>+</sup> donors, the proportion with HLA-I hyperexpression was significantly higher in the AAb<sup>++</sup> and T1D-ICI groups (94.9%, <i>p</i><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<sup>+</sup> compared with VP1<sup>−</sup> donors (45.8% vs 16%, <i>p</i><0.001).</p><h3 data-test="abstract-sub-heading">Conclusions/interpretation</h3><p>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
{"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":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Organ donor tissues were collected by the Network for Pancreatic Organ Donors with Diabetes (nPOD) from donors without diabetes (ND, <i>n</i>=76), donors expressing a single or multiple diabetes-associated autoantibodies (AAb<sup>+</sup>, <i>n</i>=20; AAb<sup>++</sup>, <i>n</i>=9) and donors with type 1 diabetes with residual insulin-containing islets (T1D-ICIs, <i>n</i>=41) or only insulin-deficient islets (T1D-IDIs, <i>n</i>=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.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Islet cell VP1 positivity was detected in most T1D-ICI donors (77.5%) vs only 38.2% of ND donors (<i>p</i><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 (<i>p</i><0.001 vs ND). Moreover, VP1<sup>+</sup> cells were detected at higher frequency in donors with HLA-I hyperexpression (<i>p</i><0.001 vs normal HLA-I). Among VP1<sup>+</sup> donors, the proportion with HLA-I hyperexpression was significantly higher in the AAb<sup>++</sup> and T1D-ICI groups (94.9%, <i>p</i><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<sup>+</sup> compared with VP1<sup>−</sup> donors (45.8% vs 16%, <i>p</i><0.001).</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>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}
Pub Date : 2025-03-17DOI: 10.1007/s00125-025-06359-w
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
Aims/hypothesis
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.
Methods
We analysed pancreas, spleen, pancreatic lymph nodes and duodenum samples from the following groups: (1) donors with type 1 diabetes (n=71) with (n=35) or without (n=36) insulin-containing islets; (2) donors with single or double islet autoantibody positivity without diabetes (n=22); and (3) autoantibody-negative donors without diabetes (control donors) (n=74). Five research laboratories participated in this collaborative effort using approaches for unbiased discovery of RNA viruses (two RNA-Seq platforms), targeted detection of Enterovirus A–D species using RT-PCR, and tests for virus growth in cell culture.
Results
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 (p<0.001) and control (non-diabetic) donors (p=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.
Conclusions/interpretation
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.
Graphical Abstract
{"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><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}
Pub Date : 2025-03-17DOI: 10.1007/s00125-025-06401-x
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
<h3 data-test="abstract-sub-heading">Aims/hypothesis</h3><p>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.</p><h3 data-test="abstract-sub-heading">Methods</h3><p>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, <i>n</i>=41) or with only insulin-deficient islets (T1D-IDI, <i>n</i>=42); donors without diabetes who are AAb-negative (ND, <i>n</i>=83); and rare donors without diabetes expressing a single AAb (AAb<sup>+</sup>, <i>n</i>=22) or multiple AAbs (AAb<sup>++</sup>, <i>n</i>=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.</p><h3 data-test="abstract-sub-heading">Results</h3><p>Detection of enterovirus indices by independent laboratories had high reproducibility, using both enterovirus-targeted and unbiased methods. T1D-ICI donors had significantly higher (<i>p</i><0.001) proportions of positive assay outcomes (58.4%) vs T1D-IDI (10.3%), ND (17.8%) and AAb-positive donors (AAb<sup>+</sup> 24.6%; AAb<sup>++</sup> 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], <i>p</i><0.0001; VP1/enterovirus-specific RT-PCR (EV-PCR), <i>p</i>=0.076; EV-PCR/HLA-I, <i>p</i>=0.016; proteomics/HLA-I, <i>p</i><0.0001; VP1/proteomics, <i>p</i>=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 (<i>p</i><0.001), 26.7% of AAb<sup>+</sup> (<i>p</i>=0.006), 28.6% of AAb<sup>++</sup> (<i>p</i>=0.023) and 0% of T1D-IDI (<i>p</i><0.001) donors.</p><h3 data-test="abstract-sub-heading">Conclusions/interpretation</h3><p>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<sup>++</sup> donors than in other groups. Their preferential detection of these indices in donors with residu
{"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":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>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.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>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, <i>n</i>=41) or with only insulin-deficient islets (T1D-IDI, <i>n</i>=42); donors without diabetes who are AAb-negative (ND, <i>n</i>=83); and rare donors without diabetes expressing a single AAb (AAb<sup>+</sup>, <i>n</i>=22) or multiple AAbs (AAb<sup>++</sup>, <i>n</i>=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.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Detection of enterovirus indices by independent laboratories had high reproducibility, using both enterovirus-targeted and unbiased methods. T1D-ICI donors had significantly higher (<i>p</i><0.001) proportions of positive assay outcomes (58.4%) vs T1D-IDI (10.3%), ND (17.8%) and AAb-positive donors (AAb<sup>+</sup> 24.6%; AAb<sup>++</sup> 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], <i>p</i><0.0001; VP1/enterovirus-specific RT-PCR (EV-PCR), <i>p</i>=0.076; EV-PCR/HLA-I, <i>p</i>=0.016; proteomics/HLA-I, <i>p</i><0.0001; VP1/proteomics, <i>p</i>=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 (<i>p</i><0.001), 26.7% of AAb<sup>+</sup> (<i>p</i>=0.006), 28.6% of AAb<sup>++</sup> (<i>p</i>=0.023) and 0% of T1D-IDI (<i>p</i><0.001) donors.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>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<sup>++</sup> 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}
Pub Date : 2025-03-15DOI: 10.1007/s00125-025-06403-9
Hyunsuk Lee, Maria Fernandes, Jeongeun Lee, Jordi Merino, Soo Heon Kwak
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.
Graphical Abstract
{"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}
Pub Date : 2025-03-12DOI: 10.1007/s00125-025-06379-6
Matilda Pitt, Abraham Olvera-Barrios, John Anderson, Louis Bolter, Ryan Chambers, Alasdair N. Warwick, Samantha Mann, Laura Webster, Jiri Fajtl, Sarah A. Barman, Catherine Egan, Adnan Tufail, Alicja R. Rudnicka, Christopher G. Owen
Aims/hypothesis
Biennial, as opposed to annual, screening for diabetic retinopathy was recently introduced within England for those considered to be at ‘low risk’. This study aims to examine the impact that annual vs biennial screening has on equitable risk of diagnosis of sight-threatening diabetic retinopathy (STDR) among people at ‘low risk’ and to develop an amelioration protocol.
Methods
In the North East London Diabetic Eye Screening Programme (NELDESP), 105,083 people without diabetic retinopathy were identified on two consecutive screening visits between January 2012 and September 2023. Data for these individuals were linked to electronic health records (EHR). Characteristics associated with subsequent STDR diagnosis were identified (including age, gender, ethnicity and diabetes duration), and logistic regression was performed to identify people who require annual screening, using variables available to the NELDESP and data from EHR. Simulations of the biennial screening protocol, and of protocols incorporating the outcomes of the logistic models and a simplified points model, were implemented, and the relative risk of STDR calculated at each screening appointment was compared amongst various population subgroups. The results were validated using data from the South East London DESP.
Results
Among the low-risk participants, there were 3694 incident STDR cases over a mean duration of 5.0 years (SD 3.4 years). Under the biennial screening protocol, almost all groups had a significantly higher risk of STDR diagnosis compared with people aged 41 years or older who were of white ethnicity and had been living with diabetes for <10 years. Compared with biennial screening, a simplified screening protocol based on age, diabetes duration and ethnicity reduced the number of delayed STDR diagnoses from 39% to 25%, with a more equitable performance across population groups, and a modest impact on screening appointment numbers (46% vs 57% reduction in annual screening appointments, respectively).
Conclusions/interpretation
A simple, clinically deliverable, personalised protocol for identifying who should be screened annually or biennially for diabetic eye disease would improve equity in risk of delayed STDR diagnosis per appointment.
Graphical Abstract
{"title":"A simple score-based strategy to improve equity of the UK biennial diabetic eye screening protocol among people deemed as low risk","authors":"Matilda Pitt, Abraham Olvera-Barrios, John Anderson, Louis Bolter, Ryan Chambers, Alasdair N. Warwick, Samantha Mann, Laura Webster, Jiri Fajtl, Sarah A. Barman, Catherine Egan, Adnan Tufail, Alicja R. Rudnicka, Christopher G. Owen","doi":"10.1007/s00125-025-06379-6","DOIUrl":"https://doi.org/10.1007/s00125-025-06379-6","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Biennial, as opposed to annual, screening for diabetic retinopathy was recently introduced within England for those considered to be at ‘low risk’. This study aims to examine the impact that annual vs biennial screening has on equitable risk of diagnosis of sight-threatening diabetic retinopathy (STDR) among people at ‘low risk’ and to develop an amelioration protocol.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>In the North East London Diabetic Eye Screening Programme (NELDESP), 105,083 people without diabetic retinopathy were identified on two consecutive screening visits between January 2012 and September 2023. Data for these individuals were linked to electronic health records (EHR). Characteristics associated with subsequent STDR diagnosis were identified (including age, gender, ethnicity and diabetes duration), and logistic regression was performed to identify people who require annual screening, using variables available to the NELDESP and data from EHR. Simulations of the biennial screening protocol, and of protocols incorporating the outcomes of the logistic models and a simplified points model, were implemented, and the relative risk of STDR calculated at each screening appointment was compared amongst various population subgroups. The results were validated using data from the South East London DESP.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Among the low-risk participants, there were 3694 incident STDR cases over a mean duration of 5.0 years (SD 3.4 years). Under the biennial screening protocol, almost all groups had a significantly higher risk of STDR diagnosis compared with people aged 41 years or older who were of white ethnicity and had been living with diabetes for <10 years. Compared with biennial screening, a simplified screening protocol based on age, diabetes duration and ethnicity reduced the number of delayed STDR diagnoses from 39% to 25%, with a more equitable performance across population groups, and a modest impact on screening appointment numbers (46% vs 57% reduction in annual screening appointments, respectively).</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>A simple, clinically deliverable, personalised protocol for identifying who should be screened annually or biennially for diabetic eye disease would improve equity in risk of delayed STDR diagnosis per appointment.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"114 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599105","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}
Pub Date : 2025-03-12DOI: 10.1007/s00125-025-06392-9
Na Zhang, Qiman Sun, Jiaxin Zhang, Ruonan Zhang, Siyi Liu, Xuelian Zhao, Jing Ma, Xiaomu Li
<h3 data-test="abstract-sub-heading">Aims/hypothesis</h3><p>Fat deposition in the pancreas is implicated in beta cell dysfunction and the progress of type 2 diabetes. However, there is limited evidence to confirm the correlation and explore how pancreatic fat links with beta cell dysfunction in human type 2 diabetes. This study aimed to examine the spatial relationship between pancreatic fat and islets in human pancreases.</p><h3 data-test="abstract-sub-heading">Methods</h3><p>Histological analysis of pancreatic specimens from 50 organ donors (15 with type 2 diabetes, 35 without) assessed pancreatic fat content variation among individuals with diabetes and its correlation with estimated beta cell mass and cell distribution within islets. Bioinformatic analysis of single-cell RNA-seq of 11 type 2 diabetic donors (from the Human Pancreatic Analysis Project database) explored the impact of high pancreatic fat content on beta cell gene expression and cell fate. Validation of bioinformatic results was performed with the above diabetic pancreases.</p><h3 data-test="abstract-sub-heading">Results</h3><p>Pancreatic fat content was higher in individuals with type 2 diabetes (10.24% [3.29–13.89%] vs 0.74% [0.34–5.11%], <i>p</i><0.001), negatively correlated with estimated beta cell mass (<i>r</i>=−0.675, <i>p</i>=0.006) and positively with alpha-to-beta cell ratio (<i>r</i>=0.608, <i>p</i>=0.016). Enrichment analysis indicated that in diabetic donors with higher pancreatic fat content, the expression of <i>ALDH1A3</i>, beta cell dedifferentiation marker, in both alpha and beta cells was significantly increased, and in beta cells, the expression of <i>NPY</i> decreased. Pseudotime analysis revealed beta cell dedifferentiation and transdifferentiation towards alpha cells in diabetic donors with higher pancreatic fat content, with decreased expression of genes related to beta cell maturation and function, including <i>INSM1</i>, <i>MafA</i> and <i>NPY</i>. Concurrently, pathways related to inflammation and immune response were activated. Histologically, pancreatic fat content correlated positively with the percentage of beta cells positive for aldehyde dehydrogenase 1 family member A3 (ALDH1A3) within the islets (<i>r</i>=0.594, <i>p</i>=0.020) and the ALDH1A3 positivity rate in beta cells (<i>r</i>=0.615, <i>p</i>=0.015). And the number of T cells adjacent to adipocytes was related to the distribution pattern of adipocytes and the dedifferentiation phenotype in islets.</p><h3 data-test="abstract-sub-heading">Conclusions/interpretation</h3><p>Higher pancreatic fat content was accompanied by increased beta cell dedifferentiation in the individuals with diabetes. Clusters of adipocytes significantly contribute to higher pancreatic fat content and immune cell recruitment. Overall, the interactions among adipocytes, immune cells and beta cells in the pancreas microenvironment might contribute to beta cell failure and dedifferentiation in type 2 diabetes.</p><h3
{"title":"Intrapancreatic adipocytes and beta cell dedifferentiation in human type 2 diabetes","authors":"Na Zhang, Qiman Sun, Jiaxin Zhang, Ruonan Zhang, Siyi Liu, Xuelian Zhao, Jing Ma, Xiaomu Li","doi":"10.1007/s00125-025-06392-9","DOIUrl":"https://doi.org/10.1007/s00125-025-06392-9","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Fat deposition in the pancreas is implicated in beta cell dysfunction and the progress of type 2 diabetes. However, there is limited evidence to confirm the correlation and explore how pancreatic fat links with beta cell dysfunction in human type 2 diabetes. This study aimed to examine the spatial relationship between pancreatic fat and islets in human pancreases.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Histological analysis of pancreatic specimens from 50 organ donors (15 with type 2 diabetes, 35 without) assessed pancreatic fat content variation among individuals with diabetes and its correlation with estimated beta cell mass and cell distribution within islets. Bioinformatic analysis of single-cell RNA-seq of 11 type 2 diabetic donors (from the Human Pancreatic Analysis Project database) explored the impact of high pancreatic fat content on beta cell gene expression and cell fate. Validation of bioinformatic results was performed with the above diabetic pancreases.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Pancreatic fat content was higher in individuals with type 2 diabetes (10.24% [3.29–13.89%] vs 0.74% [0.34–5.11%], <i>p</i><0.001), negatively correlated with estimated beta cell mass (<i>r</i>=−0.675, <i>p</i>=0.006) and positively with alpha-to-beta cell ratio (<i>r</i>=0.608, <i>p</i>=0.016). Enrichment analysis indicated that in diabetic donors with higher pancreatic fat content, the expression of <i>ALDH1A3</i>, beta cell dedifferentiation marker, in both alpha and beta cells was significantly increased, and in beta cells, the expression of <i>NPY</i> decreased. Pseudotime analysis revealed beta cell dedifferentiation and transdifferentiation towards alpha cells in diabetic donors with higher pancreatic fat content, with decreased expression of genes related to beta cell maturation and function, including <i>INSM1</i>, <i>MafA</i> and <i>NPY</i>. Concurrently, pathways related to inflammation and immune response were activated. Histologically, pancreatic fat content correlated positively with the percentage of beta cells positive for aldehyde dehydrogenase 1 family member A3 (ALDH1A3) within the islets (<i>r</i>=0.594, <i>p</i>=0.020) and the ALDH1A3 positivity rate in beta cells (<i>r</i>=0.615, <i>p</i>=0.015). And the number of T cells adjacent to adipocytes was related to the distribution pattern of adipocytes and the dedifferentiation phenotype in islets.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Higher pancreatic fat content was accompanied by increased beta cell dedifferentiation in the individuals with diabetes. Clusters of adipocytes significantly contribute to higher pancreatic fat content and immune cell recruitment. Overall, the interactions among adipocytes, immune cells and beta cells in the pancreas microenvironment might contribute to beta cell failure and dedifferentiation in type 2 diabetes.</p><h3","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"87 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599106","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}
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