Pub Date : 2025-11-17DOI: 10.1007/s00125-025-06601-5
Mia Bajramagic, Tadej Battelino, Xavier Cos, Mark Cote, Nancy Cui, Angus Forbes, Alfonso Galderisi, Lutz Heinemann, Sufyan Hussain, Jessica Imbert, Christian Holm Jönsson, Michael Joubert, Nebojša M. Lalić, Moshe Phillip, Peter Schwarz, Bart Torbeyns, Deborah J. Wake, Katerina Zakrzewska, Stefano Del Prato
{"title":"Artificial intelligence-driven clinical decision support systems to assist healthcare professionals and people with diabetes in Europe at the point of care: a Delphi-based consensus roadmap","authors":"Mia Bajramagic, Tadej Battelino, Xavier Cos, Mark Cote, Nancy Cui, Angus Forbes, Alfonso Galderisi, Lutz Heinemann, Sufyan Hussain, Jessica Imbert, Christian Holm Jönsson, Michael Joubert, Nebojša M. Lalić, Moshe Phillip, Peter Schwarz, Bart Torbeyns, Deborah J. Wake, Katerina Zakrzewska, Stefano Del Prato","doi":"10.1007/s00125-025-06601-5","DOIUrl":"https://doi.org/10.1007/s00125-025-06601-5","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"95 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145532097","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}
Aims/hypothesis: Available methods for predicting the onset and progression of diabetic kidney disease (DKD) and end-stage kidney disease (ESKD) are not yet ready for clinical application. We used a Japanese diabetes cohort study (J-DREAMS) to examine whether the Ahlqvist et al diabetes clustering is useful for stratifying DKD or ESKD outcomes independent of known risk factors in real-world settings.
Methods: Data-driven cluster analysis using k-means was performed based on GAD antibody levels, age at diagnosis, BMI, HbA1c and HOMA2 estimates of beta cell function and insulin resistance in 12,093 individuals with type 1 or type 2 diabetes. The risk of developing DKD/ESKD was analysed using Kaplan-Meier analysis and the Cox proportional hazards model.
Results: Diabetes clustering classified individuals in the J-DREAMS cohort into five subtypes, the clinical characteristics of which were comparable to those of the previously reported five subtypes. Kaplan-Meier curve analysis showed that events for chronic kidney disease (CKD) stages 3b, 4 and 5 were highest in the severe insulin-resistant diabetes subtype. The Cox proportional hazards model showed that the severe insulin-resistant diabetes subtype had significant HRs after correction for multiple confounding factors. The Cox proportional hazards model showed that each subtype had a diverse combination of factors associated with CKD stage 3b and proteinuria events.
Conclusions/interpretation: Data-driven analysis provides diabetes subtyping, which can predict the probability of developing DKD/ESKD; each subtype has diverse combinations of factors predisposing to DKD development and progression. Data-driven diabetes subtyping to predict the likelihood of developing DKD/ESKD and mitigating predisposing factors may help personalise prevention strategies.
{"title":"Diverse combination of factors associated with the development of diabetic kidney disease among data-driven diabetes subtypes: analysis of the J-DREAMS registry.","authors":"Kiriko Watanabe-Shimoji, Hayato Tanabe, Mitsuru Ohsugi, Eiryo Kawakami, Kenichi Tanaka, Junichiro J Kazama, Kohjiro Ueki, Michio Shimabukuro","doi":"10.1007/s00125-025-06594-1","DOIUrl":"https://doi.org/10.1007/s00125-025-06594-1","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Available methods for predicting the onset and progression of diabetic kidney disease (DKD) and end-stage kidney disease (ESKD) are not yet ready for clinical application. We used a Japanese diabetes cohort study (J-DREAMS) to examine whether the Ahlqvist et al diabetes clustering is useful for stratifying DKD or ESKD outcomes independent of known risk factors in real-world settings.</p><p><strong>Methods: </strong>Data-driven cluster analysis using k-means was performed based on GAD antibody levels, age at diagnosis, BMI, HbA<sub>1c</sub> and HOMA2 estimates of beta cell function and insulin resistance in 12,093 individuals with type 1 or type 2 diabetes. The risk of developing DKD/ESKD was analysed using Kaplan-Meier analysis and the Cox proportional hazards model.</p><p><strong>Results: </strong>Diabetes clustering classified individuals in the J-DREAMS cohort into five subtypes, the clinical characteristics of which were comparable to those of the previously reported five subtypes. Kaplan-Meier curve analysis showed that events for chronic kidney disease (CKD) stages 3b, 4 and 5 were highest in the severe insulin-resistant diabetes subtype. The Cox proportional hazards model showed that the severe insulin-resistant diabetes subtype had significant HRs after correction for multiple confounding factors. The Cox proportional hazards model showed that each subtype had a diverse combination of factors associated with CKD stage 3b and proteinuria events.</p><p><strong>Conclusions/interpretation: </strong>Data-driven analysis provides diabetes subtyping, which can predict the probability of developing DKD/ESKD; each subtype has diverse combinations of factors predisposing to DKD development and progression. Data-driven diabetes subtyping to predict the likelihood of developing DKD/ESKD and mitigating predisposing factors may help personalise prevention strategies.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145539254","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}
Aims/hypothesis Neuropsychological assessments and neuroimaging techniques have indicated impaired spatial working memory in adolescents with type 1 diabetes. We investigated the influence of diabetes-related factors on their spatial navigation performance. Methods Spatial navigation performance on the virtual Morris water maze task (vMWMT) was evaluated in adolescents with type 1 diabetes and compared with that of healthy control adolescents of similar age and sex. Collected data on diabetes-related variables included disease duration, diabetic ketoacidosis (DKA) at diagnosis and continuous glucose monitoring (CGM) metrics during the 2 weeks preceding the assessment, with focus upon nocturnal values measured during the night before testing. Time to first move, time to platform and path length were measured in visible and hidden platform vMWMT stages. Results The 74 study participants (age 15.6 ± 3.1 years, 45 boys) with type 1 diabetes demonstrated sex-specific patterns of spatial navigation, comparable with those observed in the healthy control group. Both the boys and girls had longer time to first move than the control groups in the visible platform stage, which assessed motor control ( p =0.036 and p =0.002, respectively). Test outcomes did not differ between the participants with and without type 1 diabetes in the hidden platform stages, which assessed spatial learning and memory. However, linear regression models adjusted for sex, age and DKA at diagnosis found that diabetes duration (β=0.464, p <0.001) independently predicted longer time to platform ( R2 =0.396, p =0.003), while nocturnal time spent in marked hypoglycaemia (β=0.397, p =0.002) predicted longer path length ( R2 =0.206, p =0.017). Conclusions/interpretation Spatial navigation performance in adolescents with type 1 diabetes is influenced by both disease duration and recent glycaemic control. Glycaemic excursions, especially during the night, were shown to impair performance. Graphical
目的/假设神经心理学评估和神经影像学技术表明1型糖尿病青少年的空间工作记忆受损。我们研究了糖尿病相关因素对他们空间导航能力的影响。方法评价1型糖尿病青少年在虚拟Morris水迷宫任务（vMWMT）中的空间导航能力，并与相同年龄和性别的健康对照组进行比较。收集的糖尿病相关变量数据包括疾病持续时间、诊断时的糖尿病酮症酸中毒（DKA）和评估前2周的连续血糖监测（CGM）指标，重点是在测试前一晚测量的夜间值。在可见和隐藏平台vMWMT阶段测量首次移动时间、到平台时间和路径长度。结果74例1型糖尿病患者（年龄15.6±3.1岁，其中45例为男孩）表现出性别特异性的空间导航模式，与健康对照组相当。在评估运动控制的可见平台阶段，男孩和女孩的第一次移动时间都比对照组长（p =0.036和p =0.002）。在评估空间学习和记忆的隐藏平台阶段，有1型糖尿病和没有1型糖尿病的参与者之间的测试结果没有差异。然而，经性别、年龄和诊断时DKA校正的线性回归模型发现，糖尿病病程（β=0.464, p <0.001）独立预测更长的到达平台时间（r2 =0.396, p =0.003），而明显低血糖的夜间时间（β=0.397, p =0.002）预测更长的路径长度（r2 =0.206, p =0.017）。结论/解释青少年1型糖尿病患者的空间导航能力受病程和近期血糖控制的影响。血糖升高，尤其是夜间血糖升高，会损害运动表现。图形化的
{"title":"The virtual Morris water maze for cognitive function assessment in adolescents with type 1 diabetes","authors":"Hussein Zaitoon, Liat Perl, Eyal Cohen-Sela, Asaf Oren, Yael Lebenthal, Avivit Brener","doi":"10.1007/s00125-025-06598-x","DOIUrl":"https://doi.org/10.1007/s00125-025-06598-x","url":null,"abstract":"Aims/hypothesis Neuropsychological assessments and neuroimaging techniques have indicated impaired spatial working memory in adolescents with type 1 diabetes. We investigated the influence of diabetes-related factors on their spatial navigation performance. Methods Spatial navigation performance on the virtual Morris water maze task (vMWMT) was evaluated in adolescents with type 1 diabetes and compared with that of healthy control adolescents of similar age and sex. Collected data on diabetes-related variables included disease duration, diabetic ketoacidosis (DKA) at diagnosis and continuous glucose monitoring (CGM) metrics during the 2 weeks preceding the assessment, with focus upon nocturnal values measured during the night before testing. Time to first move, time to platform and path length were measured in visible and hidden platform vMWMT stages. Results The 74 study participants (age 15.6 ± 3.1 years, 45 boys) with type 1 diabetes demonstrated sex-specific patterns of spatial navigation, comparable with those observed in the healthy control group. Both the boys and girls had longer time to first move than the control groups in the visible platform stage, which assessed motor control ( <jats:italic>p</jats:italic> =0.036 and <jats:italic>p</jats:italic> =0.002, respectively). Test outcomes did not differ between the participants with and without type 1 diabetes in the hidden platform stages, which assessed spatial learning and memory. However, linear regression models adjusted for sex, age and DKA at diagnosis found that diabetes duration (β=0.464, <jats:italic>p</jats:italic> <0.001) independently predicted longer time to platform ( <jats:italic>R</jats:italic> <jats:sup>2</jats:sup> =0.396, <jats:italic>p</jats:italic> =0.003), while nocturnal time spent in marked hypoglycaemia (β=0.397, <jats:italic>p</jats:italic> =0.002) predicted longer path length ( <jats:italic>R</jats:italic> <jats:sup>2</jats:sup> =0.206, <jats:italic>p</jats:italic> =0.017). Conclusions/interpretation Spatial navigation performance in adolescents with type 1 diabetes is influenced by both disease duration and recent glycaemic control. Glycaemic excursions, especially during the night, were shown to impair performance. Graphical","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"93 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531662","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 : 2025-11-13DOI: 10.1007/s00125-025-06603-3
Camille Préfontaine, Jasmine Pipella, Nayara Rampazzo Morelli, Yi-Chun Chen, C. Bruce Verchere, Peter J. Thompson
{"title":"Insulin production is sustained during DNA damage-mediated senescence in adult human beta cells","authors":"Camille Préfontaine, Jasmine Pipella, Nayara Rampazzo Morelli, Yi-Chun Chen, C. Bruce Verchere, Peter J. Thompson","doi":"10.1007/s00125-025-06603-3","DOIUrl":"https://doi.org/10.1007/s00125-025-06603-3","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"174 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498364","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 : 2025-11-11DOI: 10.1007/s00125-025-06580-7
Shivani K. Patel, Cindy S. Ma, Spiros Fourlanos, Jerry R. Greenfield
{"title":"Clinical, immunogenetic and metabolic characteristics of autoantibody-negative and autoantibody-positive type 1 diabetes","authors":"Shivani K. Patel, Cindy S. Ma, Spiros Fourlanos, Jerry R. Greenfield","doi":"10.1007/s00125-025-06580-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06580-7","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"29 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485475","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 : 2025-11-11DOI: 10.1007/s00125-025-06599-w
Viral N. Shah, Yongjin Xu, Yaghoub Dabiri, Hemanth P. Mohanadas, Alan Cheng, Timothy C. Dunn
Aims/hypothesis This study aimed to compare the predictive performance of HbA 1c and a continuous glucose monitoring (CGM)-based updated glucose management indicator (uGMI) in assessing incident diabetic retinopathy risk. Methods We used the data from a previously published longitudinal case–control study that collected CGM data for up to 7 years prior to diagnosis of incident diabetic retinopathy or no retinopathy (control participants) among adults with type 1 diabetes. Mutual information scores (MIS), receiver operating characteristics (ROC) curves and machine learning models were used to assess the associations of diabetic retinopathy with HbA 1c , uGMI and CGM-derived metrics. Results The uGMI demonstrated a stronger association with incident diabetic retinopathy (MIS 0.148) compared with HbA 1c (MIS 0.078). ROC analysis showed that uGMI had a modestly higher AUC (AUC 0.733) than HbA 1c (AUC 0.704). Decision tree models incorporating both HbA 1c and uGMI did not improve clinically significant diabetic retinopathy risk prediction. Machine learning models confirmed the better predictive value of uGMI, especially for HbA 1c values between 54 mmol/mol (7.1% NGSP) and 58 mmol/mol (7.5% NGSP), where diabetic retinopathy risk escalated significantly. Conclusions/interpretation The uGMI is a slightly stronger predictor of diabetic retinopathy risk compared with HbA 1c . HbA 1c and uGMI do not appear to be complementary for diabetic retinopathy risk prediction. Graphical
{"title":"Association of HbA1c and an updated glucose management indicator (uGMI) with incident diabetic retinopathy in adults with type 1 diabetes: a longitudinal study","authors":"Viral N. Shah, Yongjin Xu, Yaghoub Dabiri, Hemanth P. Mohanadas, Alan Cheng, Timothy C. Dunn","doi":"10.1007/s00125-025-06599-w","DOIUrl":"https://doi.org/10.1007/s00125-025-06599-w","url":null,"abstract":"Aims/hypothesis This study aimed to compare the predictive performance of HbA <jats:sub>1c</jats:sub> and a continuous glucose monitoring (CGM)-based updated glucose management indicator (uGMI) in assessing incident diabetic retinopathy risk. Methods We used the data from a previously published longitudinal case–control study that collected CGM data for up to 7 years prior to diagnosis of incident diabetic retinopathy or no retinopathy (control participants) among adults with type 1 diabetes. Mutual information scores (MIS), receiver operating characteristics (ROC) curves and machine learning models were used to assess the associations of diabetic retinopathy with HbA <jats:sub>1c</jats:sub> , uGMI and CGM-derived metrics. Results The uGMI demonstrated a stronger association with incident diabetic retinopathy (MIS 0.148) compared with HbA <jats:sub>1c</jats:sub> (MIS 0.078). ROC analysis showed that uGMI had a modestly higher AUC (AUC 0.733) than HbA <jats:sub>1c</jats:sub> (AUC 0.704). Decision tree models incorporating both HbA <jats:sub>1c</jats:sub> and uGMI did not improve clinically significant diabetic retinopathy risk prediction. Machine learning models confirmed the better predictive value of uGMI, especially for HbA <jats:sub>1c</jats:sub> values between 54 mmol/mol (7.1% NGSP) and 58 mmol/mol (7.5% NGSP), where diabetic retinopathy risk escalated significantly. Conclusions/interpretation The uGMI is a slightly stronger predictor of diabetic retinopathy risk compared with HbA <jats:sub>1c</jats:sub> . HbA <jats:sub>1c</jats:sub> and uGMI do not appear to be complementary for diabetic retinopathy risk prediction. Graphical","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"45 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485476","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}
AIMS/HYPOTHESISOur aim was to examine the presence of subclinical cardiovascular autonomic neuropathy (CAN) in a cohort of children with well-regulated type 1 diabetes by measuring baroreceptor sensitivity (BRS), QT variability index (QTVI) and heart rate variability (HRV).METHODSForty-five children (aged 6-15.99 years) with a type 1 diabetes duration of ≥5 years, and 37 healthy control children were included at baseline; and 28 and 18 children, respectively, were included at 2 year follow-up. Cardiac BRS, QTVI and HRV were measured and anthropometrical data and blood samples were collected from all study participants. Longitudinal HbA1c values from 3 months after type 1 diabetes diagnosis and continuous glucose monitoring data from the children with type 1 diabetes were also collected.RESULTSTime in normoglycaemia (TING) increased significantly from 42% to 48% between baseline and 2 year follow-up (p=0.042). No difference in BRS, QTVI or HRV were found between the study groups at baseline or follow-up. Children with type 1 diabetes with a BMI z score ≥1 showed higher QTVI compared with either lean children with diabetes or healthy control children. QTVI correlated with type 1 diabetes duration, longitudinal HbA1c AUC and cystatin C in children with type 1 diabetes at baseline, and with CV at follow-up. (r=-0.447 p=0.004, r=-0.376 p=0.017, r=-323 p=0.048, and r=0.568 p=0.01, respectively). There was also a correlation between the increase in TING between the study visits and BRS at follow-up in children with type 1 diabetes (r=0.524 p=0.031).CONCLUSIONS/INTERPRETATIONIn this well-regulated type 1 diabetes cohort we did not find manifest signs of CAN in children with type 1 diabetes. These are promising findings and should motivate further to keep striving for normoglycaemia in paediatric diabetes care. Children with both type 1 diabetes and overweight seem more susceptible to early development of CAN and might benefit from earlier and more intensive preventive targeting.
{"title":"Influence of glycaemic management and BMI on cardiac autonomic markers in children with type 1 diabetes: a prospective cohort study.","authors":"Ebba Bergdahl,Gun Forsander,Linda Milkovic,Frida Sundberg,Frida Dangardt","doi":"10.1007/s00125-025-06592-3","DOIUrl":"https://doi.org/10.1007/s00125-025-06592-3","url":null,"abstract":"AIMS/HYPOTHESISOur aim was to examine the presence of subclinical cardiovascular autonomic neuropathy (CAN) in a cohort of children with well-regulated type 1 diabetes by measuring baroreceptor sensitivity (BRS), QT variability index (QTVI) and heart rate variability (HRV).METHODSForty-five children (aged 6-15.99 years) with a type 1 diabetes duration of ≥5 years, and 37 healthy control children were included at baseline; and 28 and 18 children, respectively, were included at 2 year follow-up. Cardiac BRS, QTVI and HRV were measured and anthropometrical data and blood samples were collected from all study participants. Longitudinal HbA1c values from 3 months after type 1 diabetes diagnosis and continuous glucose monitoring data from the children with type 1 diabetes were also collected.RESULTSTime in normoglycaemia (TING) increased significantly from 42% to 48% between baseline and 2 year follow-up (p=0.042). No difference in BRS, QTVI or HRV were found between the study groups at baseline or follow-up. Children with type 1 diabetes with a BMI z score ≥1 showed higher QTVI compared with either lean children with diabetes or healthy control children. QTVI correlated with type 1 diabetes duration, longitudinal HbA1c AUC and cystatin C in children with type 1 diabetes at baseline, and with CV at follow-up. (r=-0.447 p=0.004, r=-0.376 p=0.017, r=-323 p=0.048, and r=0.568 p=0.01, respectively). There was also a correlation between the increase in TING between the study visits and BRS at follow-up in children with type 1 diabetes (r=0.524 p=0.031).CONCLUSIONS/INTERPRETATIONIn this well-regulated type 1 diabetes cohort we did not find manifest signs of CAN in children with type 1 diabetes. These are promising findings and should motivate further to keep striving for normoglycaemia in paediatric diabetes care. Children with both type 1 diabetes and overweight seem more susceptible to early development of CAN and might benefit from earlier and more intensive preventive targeting.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"1 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145491719","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 : 2025-11-10DOI: 10.1007/s00125-025-06574-5
Calum Forteath,Heather J Merchant,Cyril Kocherry,Colin E Murdoch,Jennifer Kerr,Jennifer R Gallagher,Mark L Evans,Bernard Thorens,Ulrik Pedersen-Bjergaard,Bastiaan E de Galan,Rory J McCrimmon,Alison D McNeilly,
AIMS/HYPOTHESISCVD remains the leading cause of mortality in individuals with type 1 diabetes over the age of 40 years. Although intensive insulin therapy lowers chronic hyperglycaemia and improves cardiovascular outcomes, it also increases the frequency of hypoglycaemic episodes, an emerging but poorly understood contributor to CVD risk. The mechanisms by which recurrent hypoglycaemia exacerbates cardiovascular pathology in type 1 diabetes are unknown.METHODSUsing a C57BL/J streptozocin-induced male mouse model of type 1 diabetes, combined with detailed physiological and molecular assessments, we investigated the impact of recurrent hypoglycaemia (<3.0 mmol/l) on cardiovascular structure and function using laser Doppler imaging with iontophoresis and ultrasound imaging.RESULTSType 1 diabetes induces significant microvascular endothelial dysfunction, which is worsened by recurrent hypoglycaemia. Chronic exposure to hypoglycaemia (60 episodes over 20 weeks) resulted in compensatory shifts in cardiac haemodynamics, which in type 1 diabetic mice but not non-diabetic mice resulted in early dilated cardiomyopathy. In both type 1 diabetic and non-diabetic mice, recurrent hypoglycaemia resulted in impaired systolic function during a subsequent hypoglycaemic challenge, indicating increased cardiac vulnerability despite any compensatory changes. Transcriptomic profiling of left ventricular tissue revealed that recurrent hypoglycaemia induces distinct gene expression changes involving ion homeostasis, repolarisation dynamics and microvascular signalling-molecular alterations characteristic of early diabetic cardiomyopathy.CONCLUSIONS/INTERPRETATIONThese findings provide the first in vivo evidence that recurrent hypoglycaemia synergises with hyperglycaemia to accelerate microvascular dysfunction and adverse cardiac remodelling in type 1 diabetes. This work identifies a novel mechanistic link between hypoglycaemia and diabetic heart disease, underscoring the need for therapeutic strategies that mitigate glycaemic variability without increasing the hypoglycaemic burden.DATA AVAILABILITYTranscriptomic data are available as supplementary data.
{"title":"Recurrent hypoglycaemia promotes cardiomyopathy and cardiac vulnerability in a rodent model of type 1 diabetes.","authors":"Calum Forteath,Heather J Merchant,Cyril Kocherry,Colin E Murdoch,Jennifer Kerr,Jennifer R Gallagher,Mark L Evans,Bernard Thorens,Ulrik Pedersen-Bjergaard,Bastiaan E de Galan,Rory J McCrimmon,Alison D McNeilly, ","doi":"10.1007/s00125-025-06574-5","DOIUrl":"https://doi.org/10.1007/s00125-025-06574-5","url":null,"abstract":"AIMS/HYPOTHESISCVD remains the leading cause of mortality in individuals with type 1 diabetes over the age of 40 years. Although intensive insulin therapy lowers chronic hyperglycaemia and improves cardiovascular outcomes, it also increases the frequency of hypoglycaemic episodes, an emerging but poorly understood contributor to CVD risk. The mechanisms by which recurrent hypoglycaemia exacerbates cardiovascular pathology in type 1 diabetes are unknown.METHODSUsing a C57BL/J streptozocin-induced male mouse model of type 1 diabetes, combined with detailed physiological and molecular assessments, we investigated the impact of recurrent hypoglycaemia (<3.0 mmol/l) on cardiovascular structure and function using laser Doppler imaging with iontophoresis and ultrasound imaging.RESULTSType 1 diabetes induces significant microvascular endothelial dysfunction, which is worsened by recurrent hypoglycaemia. Chronic exposure to hypoglycaemia (60 episodes over 20 weeks) resulted in compensatory shifts in cardiac haemodynamics, which in type 1 diabetic mice but not non-diabetic mice resulted in early dilated cardiomyopathy. In both type 1 diabetic and non-diabetic mice, recurrent hypoglycaemia resulted in impaired systolic function during a subsequent hypoglycaemic challenge, indicating increased cardiac vulnerability despite any compensatory changes. Transcriptomic profiling of left ventricular tissue revealed that recurrent hypoglycaemia induces distinct gene expression changes involving ion homeostasis, repolarisation dynamics and microvascular signalling-molecular alterations characteristic of early diabetic cardiomyopathy.CONCLUSIONS/INTERPRETATIONThese findings provide the first in vivo evidence that recurrent hypoglycaemia synergises with hyperglycaemia to accelerate microvascular dysfunction and adverse cardiac remodelling in type 1 diabetes. This work identifies a novel mechanistic link between hypoglycaemia and diabetic heart disease, underscoring the need for therapeutic strategies that mitigate glycaemic variability without increasing the hypoglycaemic burden.DATA AVAILABILITYTranscriptomic data are available as supplementary data.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"19 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477610","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 : 2025-11-10DOI: 10.1007/s00125-025-06582-5
Jing Cen,Anja Ivis,Svitlana Vasylovska,Kina Adjieva,Robin S Lindsay,Gunilla T Westermark,Joey Lau
AIMS/HYPOTHESISAccumulation of islet amyloid polypeptide (IAPP) and amyloid formation is associated with beta cell dysfunction and cell death in human islets and may also contribute to graft failure post stem cell-derived islet (SC-islet) transplantation. The BRICHOS domain, a secretory peptide proteolysed from the Bri2 protein, possesses chaperone activity and has been shown to inhibit fibril formation of amyloid β-peptide in the brain and IAPP in human islets. In this study, we aimed to evaluate amyloid formation in SC-islets in vitro, as well as assess the role of Bri2 BRICHOS on amyloid formation and beta cell function.METHODSHuman SC-islets were used as an in vitro model to explore the accelerated amyloid formation and to investigate the role of Bri2 BRICHOS via adenovirus-transduced overexpression. SC-islets were cultured under normal glucose conditions or metabolic stress-like conditions. Subsequently, amyloid formation was determined by staining with the amyloid-specific ligand pentameric formyl thiophene acetic acid and transmission electron microscopy. Beta cell function was assessed by static glucose-stimulated insulin secretion and insulin content. The presence of relevant proteins was evaluated by immunostaining and confocal microscopy. The mRNA expression profile of genes of interest was evaluated by qRT-PCR.RESULTSWe showed that IAPP is colocalised with insulin in SC-islet beta cells and, like human islets, SC-islets can develop amyloid under metabolic stress in vitro. Amyloid formation was increased and beta cell function was impaired in SC-islets under metabolic stress and overexpression of the Bri2 BRICHOS domain in SC-islets effectively prevented amyloid formation and partially protected beta cell function. The accentuated endogenous gene expression of ITM2B, ADAM10 and IAPP in SC-islets under the same glucose-induced metabolic stress condition was not affected by the overexpression of the Bri2 BRICHOS domain.CONCLUSIONS/INTERPRETATIONOur findings suggest that the molecular chaperone Bri2 colocalises with IAPP and insulin in SC-islet beta cells. The folding assistance has been ascribed to the BRICHOS domain in Bri2 and viral overexpression of the BRICHOS domain can prevent the formation of cytotoxic IAPP amyloid and improve beta cell function in SC-islets exposed to metabolic stress. A comprehensive analysis of SC-islet functionality excludes beta cell impairment as a cause for amyloid reduction but supports the protection against IAPP amyloid.
{"title":"Bri2 BRICHOS domain inhibits IAPP amyloid formation and improves beta cell function in stem cell-derived islets under metabolic stress.","authors":"Jing Cen,Anja Ivis,Svitlana Vasylovska,Kina Adjieva,Robin S Lindsay,Gunilla T Westermark,Joey Lau","doi":"10.1007/s00125-025-06582-5","DOIUrl":"https://doi.org/10.1007/s00125-025-06582-5","url":null,"abstract":"AIMS/HYPOTHESISAccumulation of islet amyloid polypeptide (IAPP) and amyloid formation is associated with beta cell dysfunction and cell death in human islets and may also contribute to graft failure post stem cell-derived islet (SC-islet) transplantation. The BRICHOS domain, a secretory peptide proteolysed from the Bri2 protein, possesses chaperone activity and has been shown to inhibit fibril formation of amyloid β-peptide in the brain and IAPP in human islets. In this study, we aimed to evaluate amyloid formation in SC-islets in vitro, as well as assess the role of Bri2 BRICHOS on amyloid formation and beta cell function.METHODSHuman SC-islets were used as an in vitro model to explore the accelerated amyloid formation and to investigate the role of Bri2 BRICHOS via adenovirus-transduced overexpression. SC-islets were cultured under normal glucose conditions or metabolic stress-like conditions. Subsequently, amyloid formation was determined by staining with the amyloid-specific ligand pentameric formyl thiophene acetic acid and transmission electron microscopy. Beta cell function was assessed by static glucose-stimulated insulin secretion and insulin content. The presence of relevant proteins was evaluated by immunostaining and confocal microscopy. The mRNA expression profile of genes of interest was evaluated by qRT-PCR.RESULTSWe showed that IAPP is colocalised with insulin in SC-islet beta cells and, like human islets, SC-islets can develop amyloid under metabolic stress in vitro. Amyloid formation was increased and beta cell function was impaired in SC-islets under metabolic stress and overexpression of the Bri2 BRICHOS domain in SC-islets effectively prevented amyloid formation and partially protected beta cell function. The accentuated endogenous gene expression of ITM2B, ADAM10 and IAPP in SC-islets under the same glucose-induced metabolic stress condition was not affected by the overexpression of the Bri2 BRICHOS domain.CONCLUSIONS/INTERPRETATIONOur findings suggest that the molecular chaperone Bri2 colocalises with IAPP and insulin in SC-islet beta cells. The folding assistance has been ascribed to the BRICHOS domain in Bri2 and viral overexpression of the BRICHOS domain can prevent the formation of cytotoxic IAPP amyloid and improve beta cell function in SC-islets exposed to metabolic stress. A comprehensive analysis of SC-islet functionality excludes beta cell impairment as a cause for amyloid reduction but supports the protection against IAPP amyloid.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"54 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477609","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 : 2025-11-08DOI: 10.1007/s00125-025-06579-0
F. Susan Wong, James A. Pearson, Li Wen
The NOD mouse is the best-known, although by no means the only, murine model of type 1 diabetes. In this review, we provide a historical perspective, particularly highlighting areas of progress in understanding aspects of aetiology and immune pathogenesis, and utility in helping to shape the immunotherapeutic landscape. We introduce points of interest where the NOD mouse, a much-studied model, has signposted discovery and knowledge. We discuss genetics, pancreatic islet beta cell stress, innate and adaptive immunity and autoantigens, and also focus on immunotherapeutic agents that have been tested in NOD mice and in humans. Some therapies, particularly those that are non-antigen-specific, have been more effectively signposted, while others, which include antigen-specific therapies, have not. There is an inevitable divergence between mice and humans that illustrates the need to use models appropriately. We suggest how to make use of this and other models effectively in order to maximise information and knowledge, and suggest not dismissing this important resource because of inappropriate comparisons or unrealistic expectations. Graphical
{"title":"Is the NOD mouse a good model for type 1 diabetes?","authors":"F. Susan Wong, James A. Pearson, Li Wen","doi":"10.1007/s00125-025-06579-0","DOIUrl":"https://doi.org/10.1007/s00125-025-06579-0","url":null,"abstract":"The NOD mouse is the best-known, although by no means the only, murine model of type 1 diabetes. In this review, we provide a historical perspective, particularly highlighting areas of progress in understanding aspects of aetiology and immune pathogenesis, and utility in helping to shape the immunotherapeutic landscape. We introduce points of interest where the NOD mouse, a much-studied model, has signposted discovery and knowledge. We discuss genetics, pancreatic islet beta cell stress, innate and adaptive immunity and autoantigens, and also focus on immunotherapeutic agents that have been tested in NOD mice and in humans. Some therapies, particularly those that are non-antigen-specific, have been more effectively signposted, while others, which include antigen-specific therapies, have not. There is an inevitable divergence between mice and humans that illustrates the need to use models appropriately. We suggest how to make use of this and other models effectively in order to maximise information and knowledge, and suggest not dismissing this important resource because of inappropriate comparisons or unrealistic expectations. Graphical","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"54 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472699","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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