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}
Pub Date : 2025-11-20DOI: 10.1007/s00125-025-06604-2
Amber Wouters, Pierre Lemaitre, Laure Degroote, Marijke Viaene, Marc Packbier, Nick Geukens, Chantal Mathieu, Conny Gysemans
{"title":"Redosing of anti-CD3 antibodies in NOD mice with new-onset diabetes does not alter the effect of a single treatment course","authors":"Amber Wouters, Pierre Lemaitre, Laure Degroote, Marijke Viaene, Marc Packbier, Nick Geukens, Chantal Mathieu, Conny Gysemans","doi":"10.1007/s00125-025-06604-2","DOIUrl":"https://doi.org/10.1007/s00125-025-06604-2","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"159 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145553278","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 : 2025-11-20DOI: 10.1007/s00125-025-06611-3
Peter Stenvinkel, Peter Kotanko, Johanna Painer-Gigler, Paul G. Shiels, Pieter Evenepoel, Leon Schurgers, Barbara Natterson-Horowitz, Szilvia Kalogeropoulu, Joshua Schiffman, Richard J. Johnson
This review explores the remarkable metabolic adaptations of species that thrive in extreme environments, providing insights into their resilience, flexibility and disease resistance. Species such as hibernating brown bears, migratory birds, cavefish, Greenland sharks and naked mole rats exhibit unique metabolic traits that challenge conventional paradigms of metabolic regulation. These adaptations, including resistance to hypoxia and metabolic ageing, offer potential solutions to human metabolic disorders, including obesity, type 2 diabetes and CVD. Insights from comparative physiology, particularly the mechanisms by which animals cope with food scarcity, extreme temperatures and hypoxia, could help identify novel therapeutic targets for advancing human health. For example, hibernation can serve as a model for understanding metabolic diseases, providing insights into reversible insulin resistance and energy homeostasis. This review also highlights the impact of environmental stressors, including climate change, on these species, which may jeopardise their survival despite their resilience. Accelerating anthropogenic environmental change threatens even the most resilient animal species. We call for a holistic approach to conservation and environmental protection to preserve these species and the valuable lessons they offer for managing our metabolic health. Graphical
{"title":"Comparative physiology and biomimetics in metabolic and environmental health: what can we learn from extreme animal phenotypes?","authors":"Peter Stenvinkel, Peter Kotanko, Johanna Painer-Gigler, Paul G. Shiels, Pieter Evenepoel, Leon Schurgers, Barbara Natterson-Horowitz, Szilvia Kalogeropoulu, Joshua Schiffman, Richard J. Johnson","doi":"10.1007/s00125-025-06611-3","DOIUrl":"https://doi.org/10.1007/s00125-025-06611-3","url":null,"abstract":"This review explores the remarkable metabolic adaptations of species that thrive in extreme environments, providing insights into their resilience, flexibility and disease resistance. Species such as hibernating brown bears, migratory birds, cavefish, Greenland sharks and naked mole rats exhibit unique metabolic traits that challenge conventional paradigms of metabolic regulation. These adaptations, including resistance to hypoxia and metabolic ageing, offer potential solutions to human metabolic disorders, including obesity, type 2 diabetes and CVD. Insights from comparative physiology, particularly the mechanisms by which animals cope with food scarcity, extreme temperatures and hypoxia, could help identify novel therapeutic targets for advancing human health. For example, hibernation can serve as a model for understanding metabolic diseases, providing insights into reversible insulin resistance and energy homeostasis. This review also highlights the impact of environmental stressors, including climate change, on these species, which may jeopardise their survival despite their resilience. Accelerating anthropogenic environmental change threatens even the most resilient animal species. We call for a holistic approach to conservation and environmental protection to preserve these species and the valuable lessons they offer for managing our metabolic health. Graphical","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"32 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145553309","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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