Diabetologia最新文献

{"title":"Global challenges in diabetes research and care: which way forward? An appraisal from the EASD Global Council.","authors":"Francesco Giorgino,Fawaz Alzaid,Anca Pantea Stoian,Juliana C N Chan,Linong Ji,William Lumu,Helard Manrique,Didac Mauricio,Banshi Saboo,Peter A Senior,Daisuke Yabe,Sophia Zoungas,Manuela Meireles,Chantal Mathieu,Leszek Czupryniak","doi":"10.1007/s00125-025-06504-5","DOIUrl":"https://doi.org/10.1007/s00125-025-06504-5","url":null,"abstract":"This review article, developed by the EASD Global Council, addresses the growing global challenges in diabetes research and care, highlighting the rising prevalence of diabetes, the increasing complexity of its management and the need for a coordinated international response. With regard to research, disparities in funding and infrastructure between high-income countries and low- and middle-income countries (LMICs) are discussed. The under-representation of LMIC populations in clinical trials, challenges in conducting large-scale research projects, and the ethical and legal complexities of artificial intelligence integration are also considered as specific issues. The development of global research networks and strategies for improved training, standardisation of data and enhanced accessibility to big data analytics to drive innovation and personalised medicine are recommended. With regard to diabetes care, inequalities in access to essential medications, particularly insulin and novel therapies, and disparities in healthcare infrastructure are discussed. Proposed initiatives include international support programmes, improved healthcare provider training and the inclusion of newer diabetes medications in essential drug lists. The importance of global screening programmes, a universal diabetes education curriculum and standardised healthcare checklists is also emphasised. Regarding healthcare organisation, the development of national diabetes registers, benchmarking performance across regions and strengthening international collaborations are highly advised. The role of diabetes specialists as care coordinators and the need for structured assessments to improve early intervention and long-term outcomes are also discussed. Ultimately, the EASD Global Council urges action for a unified, global approach to diabetes research and care to bridge the gap between scientific innovation and clinical practice, ensuring equitable healthcare worldwide.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"35 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025376","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":"GLP-1/GIP/GCG receptor triagonist (IUB447) enhances insulin secretion via GLP-1 receptor and Gαq signalling pathway in mice.","authors":"Pascale C F Schreier,Philipp Beyerle,Severin Boulassel,Andreas Beck,Aaron Novikoff,Peter S Reinach,Ingrid Boekhoff,Andreas Breit,Arthur Neuberger,Timo D Müller,Alberto Cebrian Serrano,Thomas Gudermann,Noushafarin Khajavi","doi":"10.1007/s00125-025-06525-0","DOIUrl":"https://doi.org/10.1007/s00125-025-06525-0","url":null,"abstract":"AIMS/HYPOTHESISUnimolecular peptides targeting the receptors for glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) have been shown to improve glycaemic management in both mice and humans. Yet the identity of the downstream signalling events mediated by these peptides remain to be elucidated. Here, we aimed to assess the mechanisms by which a validated peptide triagonist for GLP-1/GIP/GCG receptors (IUB447) stimulates insulin secretion in murine pancreatic islets.METHODSIslets were isolated from wild-type (WT), Gipr-knockout (Gipr-/-), Gcgr-knockout (Gcgr-/-), Glp-1r (also known as Glp1r)/Gipr double-knockout and Trpm5-knockout (Trpm5-/-) mice, followed by assessment of beta cell function and insulin secretion in response to mono- and multi-agonist administration. Metabolic phenotypes of WT and Trpm5-/- mice under chow and high-fat diets were investigated following triagonist application.RESULTSThe triagonist promoted glucose-stimulated insulin secretion (GSIS) to a greater degree than co-administration of conventional mono-agonists in WT mouse islets. The triagonist-induced increase in GSIS was unchanged in the absence of either Gipr or Gcgr. However, the triagonist failed to enhance insulin secretion in islets lacking both Glp-1r and Gipr and upon treatment with the GLP-1 receptor-specific antagonist exendin-3 (9-39). Similarly, the specific blocking of Gαq signalling with YM254890 or transient receptor potential melastatin 5 (TRPM5) with triphenylphosphine oxide (TPPO) suppressed the triagonist-induced enhancement of GSIS. In vivo assessment of high-fat-fed Trpm5-/- mice demonstrated the absence of triagonist-induced therapeutic effects on glycaemic management.CONCLUSIONS/INTERPRETATIONTriagonist-induced augmentation of GSIS is primarily mediated through its interaction with the GLP-1 receptor and subsequent activation of the Gαq-TRPM5 signalling pathway. Given that Gαq is a key player in the amplification of GSIS, particularly under diabetic conditions, these findings highlight a GLP-1 receptor-centric pharmacological profile that underlies the potent effects of this multi-receptor agonist.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"71 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018221","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 below range alone is insufficient to identify severe hypoglycaemia risk in type 1 diabetes-the critical role of hypoglycaemia awareness: results from the SFDT1 study.","authors":"Dulce Canha,Pratik Choudhary,Emmanuel Cosson,Isabela Banu,Sara Barraud,René Valéro,Nathalie Ronci,Blandine Delenne,Lise Dufaitre,Tiphaine Vidal-Trecan,Pauline Schaepelynck,Caroline Sanz,Sopio Tatulashvili,Gloria A Aguayo,Guy Fagherazzi,Jean-Pierre Riveline","doi":"10.1007/s00125-025-06536-x","DOIUrl":"https://doi.org/10.1007/s00125-025-06536-x","url":null,"abstract":"AIMS/HYPOTHESISSevere hypoglycaemia events (SHE) remain frequent in people with type 1 diabetes despite advanced diabetes technologies. We examined whether time below range (TBR) 3.9 mmol/l (70 mg/dl; TBR70) or 3.0 mmol/l (54 mg/dl; TBR54) is associated with future SHE risk and whether impaired awareness of hypoglycaemia (IAH) modifies this relationship.METHODSWe analysed data from participants in the Study of the French-speaking Society of Type 1 Diabetes (SFDT1) who used continuous glucose monitoring. IAH was assessed using the Gold Score (≤2, no IAH; 3, undetermined; ≥4, IAH). SHE frequency was self-reported 12 months after inclusion. We analysed associations between TBR and SHE using logistic regression models adjusted for age, sex, social vulnerability and insulin treatment, including TBR-IAH interactions. We performed spline analyses to explore non-linear patterns.RESULTSOne-year incidence of SHE was 11.7% among 848 participants (mean ± SD age 41.6 ± 13.3 years; 53.8% female sex, HbA1c 57.2 ± 10.9 mmol/mol [7.4 ± 1.0%]). Incidence by TBR70 was 12.1% for ≤1%, 10.2% for 1.1-3.9%, 10.6% for 4-6%, and 14.6% for >6%. Only those with TBR70 >6% and IAH had a significantly higher SHE risk (OR 3.32 [95% CI 1.40, 7.82]) compared with TBR70 ≤1% and no IAH. For TBR54, SHE incidence was 11.0% and 13.3% for categories <1% and ≥1%, respectively. Similarly, only individuals with TBR54≥1% and IAH had increased SHE risk (OR 2.99 [95% CI 1.46, 5.92]). Spline analysis showed low, stable SHE risk across TBR70 values in participants without IAH, with a non-linear pattern only in those with IAH.CONCLUSIONS/INTERPRETATIONTBR alone is not discriminative for high-risk SHE but combining TBR with hypoglycaemia awareness status identifies those at the highest risk for both TBR70 and TBR54.TRIAL REGISTRATIONClinicalTrials.gov NCT04657783.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"37 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018111","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":"Evaluating the role of alpha cell dysregulation in the progression to type 2 diabetes using mathematical simulations.","authors":"Vijaya Subramanian,Arthur S Sherman,Jens J Holst,Filip K Knop,Tina Vilsbøll,Jonatan I Bagger","doi":"10.1007/s00125-025-06524-1","DOIUrl":"https://doi.org/10.1007/s00125-025-06524-1","url":null,"abstract":"AIMS/HYPOTHESISAlpha cell dysregulation is an integral part of type 2 diabetes pathophysiology, increasing fasting as well as postprandial glucose concentrations. Alpha cell dysregulation occurs in tandem with the development of insulin resistance and changes in beta cell function. Our aim was to investigate, using mathematical modelling, the role of alpha cell dysregulation in beta cell compensatory insulin secretion and subsequent failure in the progression from normoglycaemia to type 2 diabetes defined by ADA criteria.METHODSWe developed a physiological model of glucose homeostasis, whereby the fast dynamics of glucose, insulin and glucagon are coupled to the dynamics of beta cell functional mass (a product of individual beta cell functional capacity and mass). Beta cell functional mass exhibits an initial compensatory increase in response to hyperglycaemia, followed by an eventual decline due to glucotoxicity. Alpha cell dysregulation, defined as increased glucagon secretion and lowered glucagon suppression resulting in hyperglycaemia, was introduced to varying extents, and simulations were carried out to assess the effects on beta cell functional mass over a 20 year period.RESULTSThe simulations were carried out under conditions of moderate, mild or no alpha cell dysregulation. The parameters representing insulin resistance, glucagon secretion and suppression for an individual with normoglycaemia obtained from previously published work were evolved over a period of 20 years to the mean values observed in type 2 diabetes. The model was validated by visually matching the beta cell functional mass obtained from the simulations of the disease progression model to previously published parameters. Those parameters were obtained from fits of a model of OGTTs to data from a cross-sectional cohort that spanned the spectrum from normoglycaemia to type 2 diabetes. We found that mild alpha cell dysregulation elicited robust beta cell compensation, resulting in controlled postprandial glucose excursions despite the development of insulin resistance. Moderate alpha cell dysregulation initially enhanced compensation but eventually accelerated the progression to type 2 diabetes. Alpha cell dysregulation impacted the time course of the standard markers of diabetes (fasting glucose, 2 h plasma glucose and HbA1c) during disease progression.CONCLUSIONS/INTERPRETATIONThe early stages of alpha cell dysregulation led to robust beta cell functional mass compensation driven by elevated fasting glucose. When the dysregulation progressed further, glucose levels rose to levels of glucotoxicity, exacerbating beta cell functional mass loss and accelerating the onset of type 2 diabetes. The various markers of diabetes (fasting glucose, 2 h plasma glucose and HbA1c) differed in terms of the prediction of timing of onset of disease, depending on the extent of alpha cell dysregulation.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"86 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018109","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":"Super effect or methodological flaw: questioning the glucagon-like peptide-1 receptor agonist cancer narrative.","authors":"Gregor A Maier,Wolfgang Rathmann,Oliver Kuß","doi":"10.1007/s00125-025-06538-9","DOIUrl":"https://doi.org/10.1007/s00125-025-06538-9","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"47 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018110","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":"bFGF rescues dysfunctional properties of adipose-derived stem cells from individuals with type 2 diabetes by modulating their miRNA profile.","authors":"Anna Civit-Urgell,Esther Peña,Maria Teresa Bejar,Fabrizio Moscatiello,Gemma Vilahur,Lina Badimon,Gemma Arderiu","doi":"10.1007/s00125-025-06533-0","DOIUrl":"https://doi.org/10.1007/s00125-025-06533-0","url":null,"abstract":"AIMS/HYPOTHESISThe aim of this study was to investigate whether basic fibroblast growth factor (bFGF) can restore the proliferation and migration capacities of adipose-derived stem cells (ASCs), which are impaired by type 2 diabetes, and improve vascular remodelling.METHODSASCs obtained from individuals with or without diabetes were cultured with 10 ng/ml bFGF for 9 days. The ASCs were phenotypically characterised and functionally tested for proliferation capacity. Differentially expressed miRNAs before and after treatment were analysed using miRNA arrays. Crosstalk between ASCs and human vascular smooth muscle cells (HVSMCs) was assessed using wound healing, transwell migration and co-culture assays. Finally, a Matrigel plug assay in nude mice was used to evaluate the contribution of ASCs to neovessel formation.RESULTSbFGF treatment significantly enhanced the proliferation and migration of ASCs from individuals with type 2 diabetes (T2DM ASCs), and altered the expression of miRNAs associated with ASC proliferation. ASCs promoted HVSMC migration and, when co-cultured, facilitated tube-like structure formation. In vivo Matrigel plug assays revealed that bFGF treatment enhanced neovessel formation. Although both non-T2DM ASCs (ASCs from individuals without type 2 diabetes) and untreated T2DM ASCs stimulated angiogenesis, bFGF-treated subcutaneous and visceral T2DM ASCs promoted even greater neovessel formation. Additionally, bFGF treatment modulated the expression of multiple angiogenesis-related miRNAs in ASCs.CONCLUSIONS/INTERPRETATIONPreconditioning T2DM ASCs with bFGF alters their miRNA profile, enhancing cell proliferation and their vascular remodelling potential. This strategy could improve the therapeutic utility of T2DM ASCs.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"122 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962704","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":"Super effect or methodological flaw: questioning the glucagon-like peptide-1 receptor agonist cancer narrative. Reply to Maier GA, Rathmann W, Kuß O [letter].","authors":"Chia-Chih Kuo,Min-Hsiang Chuang,Chun-Hsien Li,Ya-Wen Tsai,Po-Yu Huang,Hsing-Tao Kuo,Chih-Cheng Lai","doi":"10.1007/s00125-025-06526-z","DOIUrl":"https://doi.org/10.1007/s00125-025-06526-z","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"17 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962706","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":"The relationship between shrunken pore syndrome/selective glomerular hypofiltration syndromes and all-cause mortality in the Fremantle Diabetes Study Phase II.","authors":"Xincheng Gu,Yangyan Wei","doi":"10.1007/s00125-025-06531-2","DOIUrl":"https://doi.org/10.1007/s00125-025-06531-2","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"32 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960254","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":"Cideb knockdown in mice increases mitochondrial fat oxidation and reverses hepatic steatosis and insulin resistance by the plasma membrane sn-1,2-DAGs-PKCε-insulin receptor kinaseT1150 pathway.","authors":"Jie Zheng,Rafael C Gaspar,Ikki Sakuma,Brandon T Hubbard,Dongyan Zhang,Ali Nasiri,Mario Kahn,Mark Perelis,Varman T Samuel,Kitt F Petersen,Gerald I Shulman","doi":"10.1007/s00125-025-06539-8","DOIUrl":"https://doi.org/10.1007/s00125-025-06539-8","url":null,"abstract":"AIMS/HYPOTHESISCIDEB (cell death-inducing DFF45-like effector B) deficiency is associated with a reduced incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) in humans; however, the underlying mechanism responsible for this protective effect remains unclear.METHODSC57BL/6J male mice were fed a high-fat diet (HFD) to recapitulate key aspects of MASLD and hepatic insulin resistance. Cideb knockdown (KD) was achieved using a 2'-O-methoxyethyl (MOE) antisense oligonucleotide (ASO). In vivo rates of hepatic mitochondrial gluconeogenesis and tricarboxylic acid (TCA) cycle flux were assessed by Q-Flux. The Comprehensive Lab Animal Monitoring System (CLAMS) was used to evaluate rates of whole-body energy expenditure. Hepatic and peripheric insulin sensitivity were evaluated using hyperinsulinaemic-euglycaemic clamp studies combined with radio-labelled isotopes.RESULTSWe showed that Cideb ASO treatment increased rates of whole-body energy expenditure by ~25% and decreased hepatic triacylglycerol by ~65% in a HFD mouse model of MASLD compared with the wild-type mice. Cideb KD reduced hepatic fat content, which could mostly be attributed to increased rates of hepatic mitochondrial oxidation, in combination with reduced hepatic lipogenesis. Additionally, Cideb KD ameliorated HFD-induced insulin resistance, which could be attributed to decreased plasma membrane sn-1,2-diacylglycerols (DAGs)-protein kinase C (PKC)ε-insulin receptor kinase (IRK)T1150 phosphorylation in liver and skeletal muscle.CONCLUSIONS/INTERPRETATIONThese findings demonstrate that Cideb KD enhances mitochondrial fat oxidation and reduces hepatic lipogenesis, which in turn mitigates HFD-induced hepatic steatosis and insulin resistance via the plasma membrane sn-1,2-DAGs-PKCε-IRKT1150 pathway, highlighting its potential as a novel therapeutic approach for MASLD and type 2 diabetes.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"62 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995714","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":"The relationship between shrunken pore syndrome/selective glomerular hypofiltration syndromes and all-cause mortality in the Fremantle Diabetes Study Phase II. Reply to Gu X, Wei Y [letter].","authors":"David G Bruce,Wendy A Davis,S A Paul Chubb,Timothy M E Davis","doi":"10.1007/s00125-025-06532-1","DOIUrl":"https://doi.org/10.1007/s00125-025-06532-1","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"104 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960255","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}