Diabetologia最新文献

{"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}

{"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 &lt;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}

{"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":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;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.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;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.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Pancreatic fat content was higher in individuals with type 2 diabetes (10.24% [3.29–13.89%] vs 0.74% [0.34–5.11%], &lt;i&gt;p&lt;/i&gt;&lt;0.001), negatively correlated with estimated beta cell mass (&lt;i&gt;r&lt;/i&gt;=−0.675, &lt;i&gt;p&lt;/i&gt;=0.006) and positively with alpha-to-beta cell ratio (&lt;i&gt;r&lt;/i&gt;=0.608, &lt;i&gt;p&lt;/i&gt;=0.016). Enrichment analysis indicated that in diabetic donors with higher pancreatic fat content, the expression of &lt;i&gt;ALDH1A3&lt;/i&gt;, beta cell dedifferentiation marker, in both alpha and beta cells was significantly increased, and in beta cells, the expression of &lt;i&gt;NPY&lt;/i&gt; 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 &lt;i&gt;INSM1&lt;/i&gt;, &lt;i&gt;MafA&lt;/i&gt; and &lt;i&gt;NPY&lt;/i&gt;. 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 (&lt;i&gt;r&lt;/i&gt;=0.594, &lt;i&gt;p&lt;/i&gt;=0.020) and the ALDH1A3 positivity rate in beta cells (&lt;i&gt;r&lt;/i&gt;=0.615, &lt;i&gt;p&lt;/i&gt;=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.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;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.&lt;/p&gt;&lt;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}

{"title":"MAP4K4 aggravates microvascular anomalies in diabetic retinopathy in a YTHDF2-dependent manner","authors":"Qian Yang, Pei-wen Zhu, Yan-jun Wen, Ran Zhang, Wen-wen Chen, Xin Huang, Qing Chang","doi":"10.1007/s00125-025-06398-3","DOIUrl":"https://doi.org/10.1007/s00125-025-06398-3","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Signalling pathways that regulate endothelial cell (EC) dysfunction, ischaemia and inflammation play a crucial role in retinal microangiopathy such as diabetic retinopathy. MAP4K4 is highly expressed in ECs. However, the involvement of MAP4K4 in retinal vasculopathy of diabetic retinopathy remains unclear.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We analysed publicly available single-cell RNA sequencing (scRNA-seq) data from fibrovascular membranes (FVMs) from eight individuals with proliferative diabetic retinopathy (PDR) and normal retinas from 11 individuals without diabetes. Using <i>db</i>/<i>db</i> mice and human primary retinal endothelial cells (HRMECs), we further investigated the effects of MAP4K4 on retinal microangiopathy and endothelial dysfunction to explore the underlying regulatory mechanisms.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The scRNA-seq analysis revealed that <i>MAP4K4</i> was predominantly expressed in retinal ECs, with elevated expression in FVMs from individuals with PDR compared with normal retinas from individuals without diabetes. This finding was confirmed at the protein level, with MAP4K4 expression and activity being upregulated in both the FVMs of individuals with PDR and the retinas of <i>db</i>/<i>db</i> mice. Inhibition of MAP4K4 using DMX-5804 alleviated retinal microvascular leakage by enhancing the expression and integrity of junctional proteins in both ECs from <i>db</i>/<i>db</i> mice and HRMECs. Additionally, DMX-5804 reduced retinal angiogenesis by inhibiting EC migration and vascular sprouting. Mechanistically, MAP4K4 regulated EC characteristics through NF-κB signalling pathway activity. The exacerbating effect of recombinant MAP4K4 on diabetic retinopathy in <i>db</i>/<i>db</i> mice was mitigated by a p65 inhibitor, confirming the involvement of NF-κB. Moreover, MAP4K4 expression was regulated by YTH <i>N</i>⁶-methyladenosine RNA-binding protein 2 (YTHDF2), which modulates the stability of <i>MAP4K4</i> mRNA.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Our study highlights the critical role of MAP4K4 in EC dysfunction and diabetic retinal microangiopathy, providing new insights into its molecular pathogenesis. Targeting MAP4K4, particularly through modulation of the YTHDF2/MAP4K4/NF-κB axis, may provide a novel therapeutic strategy for diabetic retinopathy.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"20 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599101","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":"Research and data sovereignty in genetically admixed populations.","authors":"Linda Zollner, Rajiv Kumar, Justo Lorenzo Bermejo","doi":"10.1007/s00125-025-06383-w","DOIUrl":"https://doi.org/10.1007/s00125-025-06383-w","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604138","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":"Correction: Islet autoantibodies in Thai individuals diagnosed with type 1 diabetes before 30 years of age: a large multicentre nationwide study.","authors":"Nattachet Plengvidhya, Sarocha Suthon, Tassanee Nakdontri, Nipaporn Teerawattanapong, Saranya Ingnang, Watip Tangjittipokin","doi":"10.1007/s00125-025-06404-8","DOIUrl":"https://doi.org/10.1007/s00125-025-06404-8","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596399","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":"Rare MTNR1B variants causing diminished MT2 signalling associate with elevated HbA1c levels but not with type 2 diabetes","authors":"Kimmie V. Sørensen, Johanne M. Justesen, Lars Ängquist, Jette Bork-Jensen, Bolette Hartmann, Niklas R. Jørgensen, Jørgen Rungby, Henrik T. Sørensen, Allan Vaag, Jens S. Nielsen, Jens J. Holst, Oluf Pedersen, Allan Linneberg, Torben Hansen, Niels Grarup","doi":"10.1007/s00125-025-06381-y","DOIUrl":"https://doi.org/10.1007/s00125-025-06381-y","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>An intronic variant (rs10830963) in <i>MTNR1B</i> (encoding the melatonin receptor type 2 [MT2]) has been shown to strongly associate with impaired glucose regulation and elevated type 2 diabetes prevalence. However, <i>MTNR1B</i> missense variants have shown conflicting results on type 2 diabetes. Thus, we aimed to gain further insights into the impact of <i>MTNR1B</i> coding variants on type 2 diabetes prevalence and related phenotypes.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We conducted a cross-sectional study, performing <i>MTNR1B</i> variant burden testing of glycaemic phenotypes (<i>N</i>=248,454, without diabetes), other cardiometabolic phenotypes (<i>N</i>=330,453) and type 2 diabetes prevalence (case–control study; <i>N</i>=263,739) in the UK Biobank. Similar burden testing with glycaemic phenotypes was performed in Danish Inter99 participants without diabetes (<i>N</i>=5711), and type 2 diabetes prevalence (DD2 cohort serving as cases [<i>N</i>=2930] and Inter99 serving as controls [<i>N</i>=4243]). Finally, we evaluated the effects of <i>MTNR1B</i> variants on the melatonin-induced glucose regulation response in a recall-by-genotype study of individuals without diabetes.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>In the UK Biobank, <i>MTNR1B</i> variants were not associated with cardiometabolic phenotypes, including type 2 diabetes prevalence, except that carriers of missense <i>MTNR1B</i> variants causing impaired MT2 signalling exhibited higher HbA_1c levels compared with non-carriers (effect size, β, 0.087 SD [95% CI 0.039, 0.135]). Similarly, no significant associations were observed with phenotypes associated with glycaemic phenotypes in the Inter99 population. However, carriers of variants impairing MT2 signalling demonstrated a nominally significant lower glucose-stimulated insulin response (β −0.47 SD [95% CI −0.82, −0.11]). A reduced insulin response was also observed in carriers of variants impairing MT2 signalling (β −476.0 [95% CI −928.6, −24.4]) or the rs10830963 variant (β −390.8 [95% CI −740.1, −41.6]) compared with non-carriers after melatonin treatment.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>The higher type 2 diabetes prevalence previously observed in carriers of missense <i>MTNR1B</i> variants causing impairment in MT2 signalling was not replicated in the UK Biobank, yet carriers had elevated HbA_1c levels.</p><h3 data-test=\"abstract-sub-heading\">Data availability</h3><p>Data (Inter99 cohort and recall-by-genotype study) are available on reasonable request from the corresponding author. Requests for DD2 data are through the application form at https://dd2.dk/forskning/ansoeg-om-data. Access to UK Biobank data can be requested through the UK Biobank website (https://www.ukbiobank.ac.uk/enable-your-research).</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"4 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589632","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":"Clonal haematopoiesis of indeterminate potential: an emerging risk factor for type 2 diabetes and related complications","authors":"María A. Zuriaga, José J. Fuster","doi":"10.1007/s00125-025-06393-8","DOIUrl":"https://doi.org/10.1007/s00125-025-06393-8","url":null,"abstract":"<p>The accumulation of acquired somatic mutations is a natural consequence of ageing, but the pathophysiological implications of these mutations beyond cancer are only beginning to be understood. Most somatic mutations are functionally neutral, but a few may confer a competitive advantage to a stem cell, driving its clonal expansion. When such a mutation arises in haematopoietic stem cells, it leads to clonal haematopoiesis, in which a significant proportion of blood cells originate from the mutant stem cell and share the same mutation. Clonal haematopoiesis of indeterminate potential (CHIP), a specific subset of clonal haematopoiesis driven by myeloid leukaemia-related somatic mutations, has been linked to a higher risk of various age-related conditions, particularly CVD, by exacerbating inflammatory responses. Emerging evidence suggests that CHIP may also contribute to the pathogenesis of type 2 diabetes and some of its complications. This review synthesises current knowledge on CHIP and its potential as a novel risk factor for type 2 diabetes, highlighting the need for further research to clarify this relationship and to explore its potential value in developing personalised preventive care strategies for type 2 diabetes and related conditions.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"37 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143590278","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":"TBC1D30 regulates proinsulin and insulin secretion and is the target of a genomic association signal for proinsulin","authors":"Victoria A. Parsons, Swarooparani Vadlamudi, Kayleigh M. Voos, Abigail E. Rohy, Anne H. Moxley, Maren E. Cannon, Jonathan D. Rosen, Christine A. Mills, Laura E. Herring, K. Alaine Broadaway, Damaris N. Lorenzo, Karen L. Mohlke","doi":"10.1007/s00125-025-06391-w","DOIUrl":"https://doi.org/10.1007/s00125-025-06391-w","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Components of the insulin processing and secretion pathways remain incompletely understood. Here, we examined a genome-wide association study (GWAS) signal for plasma proinsulin levels. Lead GWAS variant rs150781447-T encodes an Arg279Cys substitution in TBC1 domain family member 30 (TBC1D30), but no role for this protein in insulin processing or secretion has been established previously. This study aimed to evaluate whether TBC1D30 drives the GWAS association signal by determining whether TBC1D30 is involved in proinsulin secretion and, if so, to examine the effects of variant alleles and potential mechanisms.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Using CRISPR/Cas9 genome editing to create double-strand breaks and prime editing to install substitutions in INS1 832/13 insulinoma cells, we generated clonal cell lines with altered TBC1D30, as well as homozygous and heterozygous lines carrying the lead GWAS variant. We characterised lines by Sanger sequencing, quantitative PCR and ELISAs to measure glucose-stimulated proinsulin and insulin secretion. We also tested the effects of <i>TBC1D30</i> knockdown on proinsulin and insulin secretion in human islets. We further assessed TBC1D30’s contribution to secretory pathways by examining the effects of altered gene function on intracellular proinsulin and insulin content and insulin localisation, and by identifying potential proteins that interact with TBC1D30 using affinity purification mass spectrometry.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Compared with mock-edited cells, cell lines with reduced <i>TBC1D30</i> expression or altered Rab GTPase-activating protein (RabGAP) domain had significantly more secreted proinsulin, 1.8- and 2.6-fold more than controls, respectively. Similarly, cells expressing the variant substitution demonstrated increased proinsulin secretion. Cell lines with a partial deletion of a critical functional domain showed 1.8-fold higher expression of <i>Tbc1d30</i> and at least 2.0-fold less secreted proinsulin. Cells with altered RabGAP domain sequence also demonstrated, to a lesser extent, changes in secreted insulin levels. <i>TBC1D30</i> knockdown in human islets resulted in increased insulin secretion with no significant effect on proinsulin secretion. The effects of altered TBC1D30 on mislocalisation of insulin, intracellular proinsulin and insulin content and the identities of interacting proteins are consistent with a role for TBC1D30 in proinsulin and insulin secretion.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>These findings suggest that effects on <i>TBC1D30</i> are responsible for the GWAS signal and that TBC1D30 plays a critical role in the secretion of mature insulin.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"40 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589850","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/s00125-025-06390-x","DOIUrl":"https://doi.org/10.1007/s00125-025-06390-x","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"27 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143570351","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}