Pub Date : 2025-11-26DOI: 10.1007/s00125-025-06615-z
So Hyun Cho, Seohyun Kim, Rosa Oh, Ji Yoon Kim, Myunghwa Jang, You-Bin Lee, Sang-Man Jin, Kyu Yeon Hur, Gyuri Kim, Jae Hyeon Kim
{"title":"High incidence of eating disorders in individuals with type 2 diabetes and their association with cardiovascular and mortality risks","authors":"So Hyun Cho, Seohyun Kim, Rosa Oh, Ji Yoon Kim, Myunghwa Jang, You-Bin Lee, Sang-Man Jin, Kyu Yeon Hur, Gyuri Kim, Jae Hyeon Kim","doi":"10.1007/s00125-025-06615-z","DOIUrl":"https://doi.org/10.1007/s00125-025-06615-z","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"23 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599318","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 : 2025-11-25DOI: 10.1007/s00125-025-06605-1
Anup K. Nair, Katiya Barkho, Koushik Ponnanna Cheranda, Michael Traurig, Jeffrey R. Sutherland, Divya Anup, Clifton Bogardus, Leslie J. Baier
Aims/hypothesis An R1420H variation in sulfonylurea receptor 1 (SUR1), a subunit of the K ATP channel, was previously identified in an Indigenous community in Arizona where a homozygous carrier (1420HH) had hyperinsulinaemic hypoglycaemia during infancy (HHI), suggestive of a K ATP channel loss of function (LoF). Interestingly, heterozygous carriers of this variation (1420RH, occurring in 3% of the community), had a twofold increased risk of type 2 diabetes. We aimed to create an isogenic induced pluripotent stem cell (iPSC)-derived pancreatic islet (SC-islet)-based platform to test whether the R1420H variant results in K ATP channel LoF, and to examine the distinct temporal effects of SUR1 1420HH and 1420RH K ATP channel variations on insulin secretion from developing and mature SC-islets. Methods Using CRISPR-Cas9, isogenic iPSCs with all three genotypes (SUR1 1420RR, 1420RH and 1420HH) were generated from two different parental Indigenous American iPSC lines (IS1, isogenic cell lines derived from parental cell line 1; and IS2, isogenic cell lines derived from parental cell line 2). These isogenic cell lines were used to generate immature SC-islets (resembling fetal islets) and mature SC-islets (resembling adult islets), which were used to assess insulin secretion dynamics during different stages of development and identify differences in gene expression by single-cell RNA-seq. This study was consistent with the CONSIDER statement for research studies among Indigenous American communities. Results Immature SUR1 1420HH SC-islets secreted 3.4-fold (IS1, p <0.001) and 4.2-fold (IS2, p =0.001) more insulin under basal conditions than normal (SUR1 1420RR) SC-islets. Modest hyperinsulinaemia was also seen in immature SUR1 1420RH SC-islets (2.2-fold [IS1] and 2.3-fold [IS2]) but the results were not statistically significant. After maturation, the 1420HH SC-islets failed to achieve glucose responsiveness whereas the 1420RH SC-islets achieved biphasic insulin secretion but had significantly lower glucose responsiveness than normal SC-islets (AUC for insulin secretion [as a % of total insulin] under high glucose challenge: 1.04 vs 0.56 in normal vs 1420RH SC-islets, p <0.001). Diazoxide reduced hyperinsulinaemia in SUR1 1420RH and 1420HH immature SC-islets, while tolbutamide elicited a greatly diminished or undetectable insulin secretory response from mature SUR1 1420RH SC-islets (13.2-fold increase in insulin secretion) and 1420HH SC-islets (1.9-fold increase) compared with normal SC-islets (31.5-fold increase). Results were directionally comparable for both IS1 and IS2 SC-islets. SUR1 1420RH SC-islets also responded to the glucokinase activator dorzagliatin with improvement in first-phase insulin secretory response (first-phase stimulation index: 3.9-fold vs 7.3-fold, p<
{"title":"Modelling the effects of human SUR1 R1420H variation on insulin secretory function using isogenic iPSC-derived pancreatic islets","authors":"Anup K. Nair, Katiya Barkho, Koushik Ponnanna Cheranda, Michael Traurig, Jeffrey R. Sutherland, Divya Anup, Clifton Bogardus, Leslie J. Baier","doi":"10.1007/s00125-025-06605-1","DOIUrl":"https://doi.org/10.1007/s00125-025-06605-1","url":null,"abstract":"Aims/hypothesis An R1420H variation in sulfonylurea receptor 1 (SUR1), a subunit of the K <jats:sub>ATP</jats:sub> channel, was previously identified in an Indigenous community in Arizona where a homozygous carrier (1420HH) had hyperinsulinaemic hypoglycaemia during infancy (HHI), suggestive of a K <jats:sub>ATP</jats:sub> channel loss of function (LoF). Interestingly, heterozygous carriers of this variation (1420RH, occurring in 3% of the community), had a twofold increased risk of type 2 diabetes. We aimed to create an isogenic induced pluripotent stem cell (iPSC)-derived pancreatic islet (SC-islet)-based platform to test whether the R1420H variant results in K <jats:sub>ATP</jats:sub> channel LoF, and to examine the distinct temporal effects of SUR1 1420HH and 1420RH K <jats:sub>ATP</jats:sub> channel variations on insulin secretion from developing and mature SC-islets. Methods Using CRISPR-Cas9, isogenic iPSCs with all three genotypes (SUR1 1420RR, 1420RH and 1420HH) were generated from two different parental Indigenous American iPSC lines (IS1, isogenic cell lines derived from parental cell line 1; and IS2, isogenic cell lines derived from parental cell line 2). These isogenic cell lines were used to generate immature SC-islets (resembling fetal islets) and mature SC-islets (resembling adult islets), which were used to assess insulin secretion dynamics during different stages of development and identify differences in gene expression by single-cell RNA-seq. This study was consistent with the CONSIDER statement for research studies among Indigenous American communities. Results Immature SUR1 1420HH SC-islets secreted 3.4-fold (IS1, <jats:italic>p</jats:italic> <0.001) and 4.2-fold (IS2, <jats:italic>p</jats:italic> =0.001) more insulin under basal conditions than normal (SUR1 1420RR) SC-islets. Modest hyperinsulinaemia was also seen in immature SUR1 1420RH SC-islets (2.2-fold [IS1] and 2.3-fold [IS2]) but the results were not statistically significant. After maturation, the 1420HH SC-islets failed to achieve glucose responsiveness whereas the 1420RH SC-islets achieved biphasic insulin secretion but had significantly lower glucose responsiveness than normal SC-islets (AUC for insulin secretion [as a % of total insulin] under high glucose challenge: 1.04 vs 0.56 in normal vs 1420RH SC-islets, <jats:italic>p</jats:italic> <0.001). Diazoxide reduced hyperinsulinaemia in SUR1 1420RH and 1420HH immature SC-islets, while tolbutamide elicited a greatly diminished or undetectable insulin secretory response from mature SUR1 1420RH SC-islets (13.2-fold increase in insulin secretion) and 1420HH SC-islets (1.9-fold increase) compared with normal SC-islets (31.5-fold increase). Results were directionally comparable for both IS1 and IS2 SC-islets. SUR1 1420RH SC-islets also responded to the glucokinase activator dorzagliatin with improvement in first-phase insulin secretory response (first-phase stimulation index: 3.9-fold vs 7.3-fold, <jats:italic>p<","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"6 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599319","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":"Time-dependent association between progression of arterial stiffness and risk of incident chronic kidney disease: a cohort study in China","authors":"Jing-li Gao, Hua Deng, Guo-Dong Wang, Hui-ling Deng, Dong-Yi Feng, Shou-ling Wu, Shuo-hua Chen, Yan-Feng Zhou","doi":"10.1007/s00125-025-06609-x","DOIUrl":"https://doi.org/10.1007/s00125-025-06609-x","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"19 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145575464","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 : 2025-11-22DOI: 10.1007/s00125-025-06608-y
Joanne Boldison, Pia Leete, Emma J. Robinson, Wendy Powell, Joanne Davies, Conor McMullan, Sophie L. Walker, Noel G. Morgan, Stephanie J. Hanna, F. Susan Wong
Aims/hypothesis The chemokine receptor C-X-C chemokine receptor type 3 (CXCR3) is a key chemoattractant molecule that facilitates the migration of activated T cells to the pancreas, leading to beta cell death. In this study, we investigated CXCR3 responses in B cells during type 1 diabetes progression. Methods Peripheral blood samples were obtained from individuals with recent-onset and long-duration type 1 diabetes, who were age- and sex-matched to non-diabetic donors. We isolated peripheral blood mononuclear cells (PBMCs) and examined changes in CXCR3 expression on lymphocytes from donors, performing multiparameter flow cytometry and functional cell culture assays. Human post-mortem pancreatic tissue was obtained from the Exeter Archival Diabetes Biobank. Immunofluorescence staining was used to assess CXCR3 expression in pancreatic tissues. Results We observed reduced CXCR3 expression on antigen-experienced B cells in individuals with a long duration of type 1 diabetes, although B cells remained responsive to IFNγ. In individuals who were recently diagnosed, IFNγ treatment resulted in increased CXCR3 expression compared with B cells from non-diabetic donors. B cells in pancreases that were recovered post-mortem from young recent-onset donors lacked CXCR3 expression, but co-staining to detect CD8 + T cells revealed a CXCR3 + CD20 + CD8 + T cell population, with their circulating counterpart showing increased CXCR3 expression. Conclusions/interpretation We conclude that the CXCR3 response in antigen-experienced B cells is dysregulated during the progression of type 1 diabetes. CXCR3 expression is limited in CD20 + B cells in pancreases from recent-onset individuals diagnosed with type 1 diabetes under 7 years of age, but evident on CD8 + T cells that express CD20. Graphical
{"title":"CXCR3 expression on antigen-experienced B cells is systemically dysregulated in type 1 diabetes","authors":"Joanne Boldison, Pia Leete, Emma J. Robinson, Wendy Powell, Joanne Davies, Conor McMullan, Sophie L. Walker, Noel G. Morgan, Stephanie J. Hanna, F. Susan Wong","doi":"10.1007/s00125-025-06608-y","DOIUrl":"https://doi.org/10.1007/s00125-025-06608-y","url":null,"abstract":"Aims/hypothesis The chemokine receptor C-X-C chemokine receptor type 3 (CXCR3) is a key chemoattractant molecule that facilitates the migration of activated T cells to the pancreas, leading to beta cell death. In this study, we investigated CXCR3 responses in B cells during type 1 diabetes progression. Methods Peripheral blood samples were obtained from individuals with recent-onset and long-duration type 1 diabetes, who were age- and sex-matched to non-diabetic donors. We isolated peripheral blood mononuclear cells (PBMCs) and examined changes in CXCR3 expression on lymphocytes from donors, performing multiparameter flow cytometry and functional cell culture assays. Human post-mortem pancreatic tissue was obtained from the Exeter Archival Diabetes Biobank. Immunofluorescence staining was used to assess CXCR3 expression in pancreatic tissues. Results We observed reduced CXCR3 expression on antigen-experienced B cells in individuals with a long duration of type 1 diabetes, although B cells remained responsive to IFNγ. In individuals who were recently diagnosed, IFNγ treatment resulted in increased CXCR3 expression compared with B cells from non-diabetic donors. B cells in pancreases that were recovered post-mortem from young recent-onset donors lacked CXCR3 expression, but co-staining to detect CD8 <jats:sup>+</jats:sup> T cells revealed a CXCR3 <jats:sup>+</jats:sup> CD20 <jats:sup>+</jats:sup> CD8 <jats:sup>+</jats:sup> T cell population, with their circulating counterpart showing increased CXCR3 expression. Conclusions/interpretation We conclude that the CXCR3 response in antigen-experienced B cells is dysregulated during the progression of type 1 diabetes. CXCR3 expression is limited in CD20 <jats:sup>+</jats:sup> B cells in pancreases from recent-onset individuals diagnosed with type 1 diabetes under 7 years of age, but evident on CD8 <jats:sup>+</jats:sup> T cells that express CD20. Graphical","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"199 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567096","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 : 2025-11-22DOI: 10.1007/s00125-025-06606-0
Elisabeth R. Trimble, David I. W. Phillips, Shitaye A. Balcha
{"title":"From malnutrition-related diabetes mellitus to ‘type 5 diabetes’: phenotypic variation, not reclassification. Reply to Gupta L, Misra A [letter]","authors":"Elisabeth R. Trimble, David I. W. Phillips, Shitaye A. Balcha","doi":"10.1007/s00125-025-06606-0","DOIUrl":"https://doi.org/10.1007/s00125-025-06606-0","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"170 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567098","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 : 2025-11-22DOI: 10.1007/s00125-025-06600-6
Adam G. Maynard, Raghav Bhardwaj, Thouis R. Jones, Melina Claussnitzer
{"title":"Bridging the variant-to-function gap in type 2 diabetes: advances and challenges","authors":"Adam G. Maynard, Raghav Bhardwaj, Thouis R. Jones, Melina Claussnitzer","doi":"10.1007/s00125-025-06600-6","DOIUrl":"https://doi.org/10.1007/s00125-025-06600-6","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"104 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567095","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 : 2025-11-21DOI: 10.1007/s00125-025-06610-4
Jørn Nerup,Åke Lernmark
{"title":"The rise and fall of a paradigm and conceiving a new hypothesis for type 1 diabetes.","authors":"Jørn Nerup,Åke Lernmark","doi":"10.1007/s00125-025-06610-4","DOIUrl":"https://doi.org/10.1007/s00125-025-06610-4","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"79 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559045","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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