Diabetologia最新文献

{"title":"Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus","authors":"Christopher T. A. Lewis, Roger Moreno-Justicia, Lola Savoure, Enrique Calvo, Agata Bak, Jenni Laitila, Robert A. E. Seaborne, Steen Larsen, Hiroyuki Iwamoto, Marina Cefis, Jose A. Morais, Gilles Gouspillou, Jorge Alegre-Cebollada, Thomas J. Hawke, Jesús Vazquez, Miquel Adrover, Vincent Marcangeli, Rami Hammad, Jordan Granet, Pierrette Gaudreau, Mylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, Atul S. Deshmukh, Julien Ochala","doi":"10.1007/s00125-025-06436-0","DOIUrl":"https://doi.org/10.1007/s00125-025-06436-0","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Disrupted energy balance is critical for the onset and development of type 2 diabetes mellitus. Understanding of the exact underlying metabolic mechanisms remains incomplete, but skeletal muscle is thought to play an important pathogenic role. As the super-relaxed state of its most abundant protein, myosin, regulates cellular energetics, we aimed to investigate whether it is altered in individuals with type 2 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We used vastus lateralis biopsy specimens (obtained from patients with type 2 diabetes and control participants with similar characteristics), and ran a combination of structural and functional assays consisting of loaded 2′- (or 3′)-<i>O-</i>(<i>N-</i>methylanthraniloyl)-ATP (Mant-ATP) chase experiments, x-ray diffraction and LC-MS/MS proteomics in isolated muscle fibres.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Our studies revealed a greater muscle myosin super-relaxation and decreased ATP demand in male participants with type 2 diabetes than in control participants. Subsequent proteomic analyses indicated that these (mal)adaptations probably originated from remodelled sarcomeric proteins and greater myosin glycation levels in patients than in control participants.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Overall, our findings indicate a complex molecular dysregulation of myosin super-relaxed state and energy consumption in male participants with type 2 diabetes. Ultimately, pharmacological targeting of myosin could benefit skeletal muscle and whole-body metabolic health through enhancement of ATP consumption.</p><h3 data-test=\"abstract-sub-heading\">Data availability</h3><p>The raw MS data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD053022.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"217 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884450","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":"Pancreatic exocrine damage induces beta cell stress in zebrafish larvae","authors":"Noura Faraj, Willem M. H. Hoogaars, B. H. Peter Duinkerken, Anouk H. G. Wolters, Kim Kats, Mette C. Dekkers, Arnaud Zaldumbide, Ben N. G. Giepmans","doi":"10.1007/s00125-025-06432-4","DOIUrl":"https://doi.org/10.1007/s00125-025-06432-4","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Excessive endoplasmic reticulum (ER) stress in beta cells can impair proliferation and contribute to autoimmune responses such as the destruction of beta cells in type 1 diabetes. Exocrine–beta cell interactions affect beta cell growth and function. Notably, exocrine abnormalities are frequently observed alongside overloaded beta cells in different types of diabetes, suggesting that exocrine stress may induce beta cell ER stress and loss. While a cause–consequence relationship between exocrine stress and beta cell function cannot be addressed in humans, it can be studied in a zebrafish model. Larvae develop a pancreas with a human-like morphology by 120 h post-fertilisation, providing a valuable dynamic model for studying pancreatic interactions. Our aim was to target exocrine cells specifically and address beta cell status using transgenic zebrafish models and reporters.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>To explore the impact of exocrine damage on beta cell fitness, we generated a novel zebrafish model allowing exocrine pancreas ablation, using a nifurpirinol–nitroreductase system. We subsequently assessed the in vivo effects on beta cells by live-monitoring dynamic cellular events, such as ER stress, apoptosis and changes in beta cell number and volume.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Exocrine damage in zebrafish decreased pancreas volume by approximately 50% and changed its morphology. The resulting exocrine damage induced ER stress in 60–90% of beta cells and resulted in a ~50% reduction in their number.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>The zebrafish model provides a robust platform for investigating the interplay between exocrine cells and beta cells, thereby enhancing further insights into the mechanisms driving pancreatic diseases such as type 1 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"43 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884456","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":"Severe hypoglycaemia is associated with increased risk of adverse cardiovascular complications in adults with type 1 diabetes: risk mitigation using intermittently scanned continuous glucose monitoring","authors":"Katarina Eeg-Olofsson, David Nathanson, Tim Spelman, Mattias Kyhlstedt, Alexander Seibold, Fleur Levrat-Guillen, Jan Bolinder","doi":"10.1007/s00125-025-06438-y","DOIUrl":"https://doi.org/10.1007/s00125-025-06438-y","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>It has been proposed that severe hypoglycaemia events (SHE) may increase the risk of adverse CVD complications in adults with type 1 diabetes. The aim of this study was to evaluate the risk of CVD complications following SHE in a large cohort of adults with type 1 diabetes, and to compare the risk of post-SHE CVD complications for users of intermittently scanned continuous glucose monitoring (isCGM) vs users of blood glucose monitoring (BGM).</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>This comparative retrospective cohort study used data from the Swedish National Diabetes Register and the Swedish National Patient Register. We identified people with type 1 diabetes who had a hospitalisation for CVD complications. Rates of hospitalisation were compared between those with an index SHE and those without, and within isCGM or BGM subgroups. The study baseline was date of the first SHE prior to the isCGM index date.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>We identified 14,829 adults with type 1 diabetes with up to 2 years of follow-up, of which 1313 had an index SHE. In the full cohort, the relative rate of hospitalisations for CVD complications was 2.06-fold (95% CI 1.48, 2.85) in those with prior SHE. Of these 1313 participants with prior SHE, 970 were using isCGM and 343 were using BGM. Hospitalisations for post-SHE CVD complications were significantly lower for isCGM users (5.40 per 100 person-years of follow-up; 95% CI 4.59, 6.31) compared with BGM control participants (14.23 per 100 person-years of follow-up; 95% CI 11.95, 16.82), which represents a 78% relative reduction in rates of post-SHE CVD complications for isCGM users (relative rate 0.22; 95% CI 0.11, 0.43; <i>p</i>&lt;0.001), after adjustment for confounders.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>In adults with type 1 diabetes, SHE is associated with an increased risk of hospitalisation for adverse CVD complications. This risk is significantly reduced in isCGM users compared with BGM control participants.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"6 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866702","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":"RFX3 is essential for the generation of functional human pancreatic islets from stem cells","authors":"Bushra Memon, Noura Aldous, Ahmed K. Elsayed, Sadaf Ijaz, Sikander Hayat, Essam M. Abdelalim","doi":"10.1007/s00125-025-06424-4","DOIUrl":"https://doi.org/10.1007/s00125-025-06424-4","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>The role of regulatory factor X 3 (RFX3) in human pancreatic islet development has not been explored. This study aims to investigate the function of RFX3 in human pancreatic islet development using human islet organoids derived from induced pluripotent stem cells (iPSCs), hypothesising that RFX3 regulates human islet cell differentiation.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We generated <i>RFX3</i> knockout (<i>RFX3</i> KO) iPSC lines using CRISPR/Cas9 and differentiated them into pancreatic islet organoids. Various techniques were employed to assess gene expression, cell markers, apoptosis, proliferation and glucose-stimulated insulin secretion. Single-cell RNA-seq datasets from human embryonic stem cell-derived pancreatic islet differentiation were re-analysed to investigate <i>RFX3</i> expression in specific cell populations at various developmental stages. Furthermore, bulk RNA-seq was conducted to further assess transcriptomic changes. RFX3 overexpression was implemented to reverse dysregulated gene expression.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>RFX3 was found to be highly expressed in pancreatic endocrine cell populations within pancreatic progenitors (PPs), endocrine progenitors (EPs) and mature islet stages derived from iPSCs. Single-cell RNA-seq further confirmed RFX3 expression across different endocrine cell clusters during differentiation. The loss of <i>RFX3</i> disrupted pancreatic endocrine gene regulation, reduced the number of hormone-secreting islet cells and impaired beta cell function and insulin secretion. Despite a significant reduction in the expression levels of pancreatic islet hormones, the pan-endocrine marker chromogranin A remained unchanged at both EP and islet stages, likely due to an increase in the abundance of enterochromaffin cells (ECs). This was supported by our findings of high EC marker expression levels in <i>RFX3</i> KO EPs and islets. In addition, <i>RFX3</i> loss led to smaller islet organoids, elevated thioredoxin-interacting protein levels and increased apoptosis in EPs and islets. Furthermore, <i>RFX3</i> overexpression rescued the expression of dysregulated genes in <i>RFX3</i> KO at the PP and EP stages.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>These findings underscore the crucial role of RFX3 in regulating human islet cell differentiation and its role in suppressing EC specification. These insights into RFX3 function have implications for understanding islet biology and potential diabetes susceptibility.</p><h3 data-test=\"abstract-sub-heading\">Data availability</h3><p>The RNA-seq datasets have been submitted to the Zenodo repository and can be accessed via the following links: DOI https://doi.org/10.5281/zenodo.13647651 (PPs); and DOI https://doi.org/10.5281/zenodo.13762055 (SC-islets).</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"108 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862960","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":"DNA methylation and 28 year incidence of two neuropathy phenotypes in type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complications cohort study","authors":"Jiayi Zhou, Josyf C. Mychaleckyj, Suna Onengut-Gumuscu, Trevor J. Orchard, Tina Costacou, Rachel G. Miller","doi":"10.1007/s00125-025-06427-1","DOIUrl":"https://doi.org/10.1007/s00125-025-06427-1","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Diabetic peripheral neuropathy (DPN) and neuropathic pain (NP) are common complications of type 1 diabetes that can greatly affect quality of life. Studying DNA methylation (DNAm) may help identify potential therapeutic targets; however, epigenome-wide association studies (EWAS) of DPN and NP are lacking. We thus performed prospective EWAS of 28 year DPN and NP incidence in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset (&lt;17 years) type 1 diabetes.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;DPN was defined as two or more of the following criteria: symptoms consistent with DPN; decreased tendon reflexes; or abnormal sensory examination. NP was reported as burning, aching or stabbing pain in the feet during an EDC examination or on the Michigan Neuropathy Screening Instrument (MNSI). The time of the first available blood-derived DNA specimen collected between 1988–1998 was considered the analytic ‘baseline’ (mean age 27 years; diabetes duration 19 years). After quality control, DNAm (EPIC array) at 683,597 CpGs was analysed in Cox models for time-to-DPN in 282 individuals free of DPN at baseline and time to NP in 365 individuals free of NP at baseline. False discovery rate (FDR) &lt;0.05 was considered statistically significant. We also identified differentially methylated regions (DMRs), functional interaction networks and genetic variants associated with DNAm (methylation quantitative trait loci [meQTLs]), and performed Mendelian randomisation (MR) to assess evidence of causality.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Over 28 years, 154 individuals (54.6%) developed DPN and 148 (40.5%) developed NP. Greater methylation at three CpGs was significantly associated (FDR≤0.05) with reduced hazard of DPN: cg06163904 (&lt;i&gt;CHMP6&lt;/i&gt;); cg10835127 (&lt;i&gt;CACNA1B&lt;/i&gt;); and cg18945945 (&lt;i&gt;PKNOX1&lt;/i&gt;). CpG associations with DPN remained similar after adjustment for clinical risk factors. We identified 75 meQTLs for cg18945945 in the &lt;i&gt;PKNOX1&lt;/i&gt; region, 59 of which were validated in an external diabetes cohort. One-sample MR provided nominal evidence for a potentially causal association between cg18945945 and DPN (&lt;i&gt;p&lt;/i&gt;=0.01). While no individual CpGs were significantly associated with NP, there were 49 NP-associated DMRs.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;Our study identified associations between DNAm and 28 year incidence of DPN and NP at several biologically plausible loci. Most notably, we identified a novel association between DNAm of &lt;i&gt;PKNOX1&lt;/i&gt; and future DPN, including evidence of a genetic influence on &lt;i&gt;PKNOX1&lt;/i&gt; methylation that was validated in an external diabetes cohort. &lt;i&gt;PKNOX1&lt;/i&gt; has previously been implicated in drug-induced neuropathy; our results provide strong evidence that epigenetic regulation of &lt;i&gt;PKNOX1&lt;/i&gt; may also play a functional role in the development of ","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"18 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862959","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 and all-cause mortality in people with type 2 diabetes and normal renal function: the Fremantle Diabetes Study Phase II","authors":"David G. Bruce, Wendy A. Davis, S. A. Paul Chubb, Timothy M. E. Davis","doi":"10.1007/s00125-025-06430-6","DOIUrl":"https://doi.org/10.1007/s00125-025-06430-6","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Estimated GFRs utilising creatinine- (eGFR_creat) or cystatin C-based (eGFR_cyst) equations can generate discrepant results that are associated with clinical outcomes. A low eGFR_cyst/eGFR_creat ratio (&lt;0.60), reflecting a pathological glomerular state termed shrunken pore syndrome (SPS), has been associated with excess mortality in some clinical situations including diabetes. The aim of the present study was to explore this association in a longitudinal observational study of type 2 diabetes with special reference to participants with normal renal function.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Of 1481 Fremantle Diabetes Study Phase II participants with type 2 diabetes, aged ≥17 years, 1466 had eGFR_creat and eGFR_cyst assessed as part of the baseline assessment and were followed for 10 years or until death, whichever came first. Cox regression modelling was used to determine independent associates of death excluding eGFR; eGFR_cyst/eGFR_creat ratio was then added to this model separately as a categorical or continuous variable. These analyses were also conducted in a subgroup (<i>n</i>=754) of participants with normal renal function (eGFR_creat ≥60 ml/min per 1.73 m² and urinary albumin/creatinine ratio &lt;3 mg/mmol) at baseline.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>At entry, the participants had a mean age of 65.9 years, 51.8% were male, the median diabetes duration was 9.0 years and 10.4% had eGFR_cyst/eGFR_creat ratio &lt;0.60 (the definition of SPS). There were 384 deaths (26.2%) during follow-up. The eGFR_cyst/eGFR_creat ratio was independently, significantly and negatively associated with death (adjusted HR [95% CI] 0.91 [0.85, 0.97] for an increase of 0.1, <i>p</i>=0.004). Of eGFR_cyst/eGFR_creat ratio categories, only &lt;0.60 added significantly to the most parsimonious Cox model of time to death (HR [95% CI] 1.56 [1.07, 2.29], <i>p</i>=0.021). In those with normal renal function, 123 (16.3%) died during follow-up. An eGFR_cyst/eGFR_creat ratio &lt;0.60, observed in 57 (7.6%), was also independently associated with mortality (HR [95% CI] 2.55 [1.34, 4.84], <i>p</i>=0.004).</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>A low eGFR_cyst/eGFR_creat ratio is independently associated with mortality in type 2 diabetes, including in people without conventional markers of diabetic kidney disease. The presence of SPS may add clinical value to the risk assessment of people with type 2 diabetes regardless of renal status.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"14 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853530","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":"Diabetes and natural and man-made disasters: prevention, preparation, response and recovery","authors":"Andrew J. M. Boulton, Alicia J. Jenkins, Brij Makkar, Boris Mankovsky, Merhawit A. Abera, Solomon Tesfaye","doi":"10.1007/s00125-025-06406-6","DOIUrl":"https://doi.org/10.1007/s00125-025-06406-6","url":null,"abstract":"<p>Both the global prevalence of diabetes and the frequency of natural and man-made disasters are increasing. Of all chronic diseases, the consequences of sudden loss of medical supplies are most serious for those with diabetes, with people living with type 1 diabetes being at risk of death within a few days without insulin. This review considers how to prepare for and respond to sudden reductions in medical supplies to those with diabetes. Recent experiences with the COVID-19 pandemic in India, the war in Ukraine and the war/blockade in the Tigray region of Ethiopia are described, and the importance of prevention, preparedness, response and recovery are discussed. It is hoped that lessons from these and other disasters and ongoing advocacy and other actions may help to mitigate the risks of significant morbidity and mortality for people with diabetes in disaster-impacted regions across the world.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"1 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836691","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":"Exercise-induced meteorin-like protein protects human pancreatic beta cells from cytokine-induced apoptosis","authors":"José Maria Costa-Junior, Alexandra Coomans de Brachène, Anyïshai E. Musuaya, Priscila L. Zimath, Eugenia Martin-Vazquez, Junior G. Oliveira, Julie Carpentier, Vitalie Faoro, Malgorzata Klass, Miriam Cnop, Decio L. Eizirik","doi":"10.1007/s00125-025-06426-2","DOIUrl":"https://doi.org/10.1007/s00125-025-06426-2","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Inflammation-driven pancreatic beta cell death is a hallmark of type 1 diabetes progression. We have previously shown that serum obtained from individuals after high-intensity interval training prevents cytokine-induced human beta cell apoptosis, but the mediators of this beneficial effect remain to be characterised. In this study we evaluated the role of exercise-induced meteorin-like protein (Metrnl) in human beta cell protection.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Human EndoC-βH1 cells and induced pluripotent stem cell (iPSC)-derived islets were exposed to proinflammatory cytokines and treated with serum collected before and after high-intensity interval training, with and without Metrnl-neutralising antibodies. The effects of Metrnl on apoptosis, insulin secretion and chemokine CXCL10 gene and protein expression were assessed.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Post-exercise serum had an increased concentration of Metrnl compared with pre-exercise level serum, resulting in a 46% reduction in cytokine-induced beta cell death. Additionally, direct treatment with recombinant Metrnl at concentrations of 100 ng/ml and 200 ng/ml reduced cytokine-induced cell death by 24% and 41%, respectively, in EndoC-βH1 cells, with similar results obtained in iPSC-derived islets. Metrnl treatment also preserved insulin secretion under inflammatory stress. These effects were associated with a decrease in <i>CXCL10</i> mRNA expression and protein release. Blocking Metrnl with a neutralising antibody eliminated the protective effects of serum from trained individuals on EndoC-βH1 cells exposure to proinflammatory cytokines.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Our findings reveal that the exerkine Metrnl is a key mediator of the beneficial effects of exercise on pancreatic beta cells, suggesting that Metrnl is a potential therapeutic target for preserving human beta cell function and survival in type 1 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"10 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822732","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 genetic architecture of type 1 diabetes over time: how well can we rely on past data to predict the future?","authors":"Jose Zapardiel-Gonzalo,Anette-Gabriele Ziegler,Ezio Bonifacio","doi":"10.1007/s00125-025-06422-6","DOIUrl":"https://doi.org/10.1007/s00125-025-06422-6","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"108 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827111","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":"Alterations in cerebral perfusion and substrate metabolism in type 2 diabetes: interactions with APOE-ε4","authors":"Martin Schain, Edvin Johansson, Iina Laitinen, Anna Frödén Löwenmark, Mark Lubberink, Anders Gummesson, Torsten Danfors, Pirjo Nuutila, Russell Esterline, Lars Johansson, Jan Oscarsson, Kerstin Heurling","doi":"10.1007/s00125-025-06405-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06405-7","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Epidemiological studies indicate that type 2 diabetes increases the risk for Alzheimer’s disease. Alterations in cerebral metabolism have been proposed as a potential mechanism underlying this association. A better understanding of these metabolic changes may elucidate potential pathways linking type 2 diabetes to Alzheimer’s disease. The aim of the current exploratory study was to investigate whether cerebral metabolism, including glucose and fatty acid uptake as well as cerebral blood flow, is altered in individuals with type 2 diabetes compared with both overweight individuals and lean control individuals.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;This exploratory study included 38 participants (ten with type 2 diabetes, 13 overweight individuals and 15 lean control individuals). Brain metabolism was assessed using multiple imaging techniques: [&lt;sup&gt;18&lt;/sup&gt;F]fluorodeoxyglucose and [&lt;sup&gt;18&lt;/sup&gt;F]fluoro-6-thiaheptadecanoic acid positron emission tomography for glucose and fatty acid uptake; arterial spin-labelling MRI for cerebral perfusion; and &lt;sup&gt;1&lt;/sup&gt;H-magnetic resonance spectroscopy for specific metabolites. Neurodegeneration markers were evaluated from lumbar puncture samples. Group comparisons were assessed using one-way ANOVA and unpaired &lt;i&gt;t&lt;/i&gt; tests, and correlations were assessed with linear regression.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Individuals with type 2 diabetes exhibited lower cerebral glucose uptake compared with both lean and overweight groups (&lt;i&gt;p&lt;/i&gt;&lt;0.01). Cerebral perfusion was reduced in both participants with type 2 diabetes and overweight participants relative to lean control participants (&lt;i&gt;p&lt;/i&gt;&lt;0.01). Both glucose uptake and perfusion correlated negatively with HOMA-IR, insulin and HbA&lt;sub&gt;1c&lt;/sub&gt; levels (&lt;i&gt;p&lt;/i&gt;&lt;0.001–&lt;i&gt;p&lt;/i&gt;&lt;0.05). White matter fatty acid uptake was elevated in the diabetes group compared with the lean group (&lt;i&gt;p&lt;/i&gt;&lt;0.05). Post hoc analyses revealed that lean &lt;i&gt;APOE-ε4&lt;/i&gt; carriers had increased fatty acid uptake in the entire brain relative to lean non-carriers. Among non-carriers of &lt;i&gt;APOE-ε4&lt;/i&gt;, those with type 2 diabetes showed higher fatty acid uptake than lean control individuals (&lt;i&gt;p&lt;/i&gt;&lt;0.01–&lt;i&gt;p&lt;/i&gt;&lt;0.05), and this uptake correlated positively with HOMA-IR, insulin and HbA&lt;sub&gt;1c&lt;/sub&gt; levels (&lt;i&gt;p&lt;/i&gt;&lt;0.05).&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;Type 2 diabetes was associated with decreased cerebral perfusion and glucose uptake but increased fatty acid uptake in white matter. The elevated fatty acid uptake observed both in individuals with type 2 diabetes and in &lt;i&gt;APOE-ε4&lt;/i&gt; carriers suggests a common metabolic dysfunction for these Alzheimer’s disease risk factors and suggests that targeting cerebral metabolic dysfunction, particularly fatty acid metabolism, could be a potential strategy for reducing the risk for ","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"108 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819426","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}