Diabetologia最新文献

{"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}

{"title":"The genetics of low and high birthweight and their relationship with cardiometabolic disease","authors":"Gunn-Helen Moen, Liang-Dar Hwang, Caroline Brito Nunes, Nicole M. Warrington, David M. Evans","doi":"10.1007/s00125-025-06420-8","DOIUrl":"https://doi.org/10.1007/s00125-025-06420-8","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Low birthweight infants are at increased risk not only of mortality, but also of type 2 diabetes mellitus and CVD in later life. At the opposite end of the spectrum, high birthweight infants have increased risk of birth complications, such as shoulder dystocia, neonatal hypoglycaemia and obesity, and similarly increased risk of type 2 diabetes mellitus and CVD. However, previous genome-wide association studies (GWAS) of birthweight in the UK Biobank have primarily focused on individuals within the ‘normal’ range and have excluded individuals with high and low birthweight (&lt;2.5 kg or &gt;4.5 kg). The aim of this study was to investigate genetic variation associated within the tail ends of the birthweight distribution, to: (1) see whether the genetic factors operating in these regions were different from those that explained variation in birthweight within the normal range; (2) explore the genetic correlation between extremes of birthweight and cardiometabolic disease; and (3) investigate whether analysing the full distribution of birthweight values, including the extremes, improved the ability to detect genuine loci in GWAS.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;We performed case–control GWAS analysis of low (&lt;2.5 kg) and high (&gt;4.5 kg) birthweight in the UK Biobank using REGENIE software (&lt;i&gt;N&lt;/i&gt;&lt;sub&gt;low&lt;/sub&gt;=20,947; &lt;i&gt;N&lt;/i&gt;&lt;sub&gt;high&lt;/sub&gt;=12,715; &lt;i&gt;N&lt;/i&gt;&lt;sub&gt;controls&lt;/sub&gt;=207,506) and conducted three continuous GWAS of birthweight, one including the full range of birthweights, one involving a truncated GWAS including only individuals with birthweights between 2.5 and 4.5 kg and a third GWAS that winsorised birthweight values &lt;2.5 kg and &gt;4.5 kg. Additionally, we performed bivariate linkage disequilibrium (LD) score regression to estimate the genetic correlation between low/normal/high birthweight and cardiometabolic traits.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Bivariate LD score regression analyses suggested that high birthweight had a mostly similar genetic aetiology to birthweight within the normal range (genetic correlation coefficient [&lt;i&gt;r&lt;/i&gt;&lt;sub&gt;G&lt;/sub&gt;]=0.91, 95% CI 0.83, 0.99), whereas there was more evidence for a separate set of genes underlying low birthweight (&lt;i&gt;r&lt;/i&gt;&lt;sub&gt;G&lt;/sub&gt;=−0.74, 95% CI 0.66, 0.82). Low birthweight was also significantly positively genetically correlated with most cardiometabolic traits and diseases we examined, whereas high birthweight was mostly positively genetically correlated with adiposity and anthropometric-related traits. The winsorisation strategy performed best in terms of locus detection, with the number of independent genome-wide significant associations (&lt;i&gt;p&lt;/i&gt;&lt;5×10&lt;sup&gt;−8&lt;/sup&gt;) increasing from 120 genetic variants at 94 loci in the truncated GWAS to 270 genetic variants at 178 loci, including 27 variants at 25 loci that had not been identified in previous birthweight GWAS. Th","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"183 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819411","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":"Metabolic effects of 3-hydroxybutyrate infusion in individuals with type 1 diabetes compared with healthy control participants: a randomised crossover trial showing intact feedback suppression of lipolysis","authors":"Maj Bangshaab, Mads V. Svart, Nikolaj Rittig, Mette G. B. Pedersen, Jens Voigt, Niels Jessen, Niels Møller","doi":"10.1007/s00125-025-06423-5","DOIUrl":"https://doi.org/10.1007/s00125-025-06423-5","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Diabetic ketoacidosis remains a severe complication in type 1 diabetes, arising from insufficient insulin levels and accelerated lipolytic rate, leading to increased β-oxidation of NEFA and ketone body production in the liver. The ketone body 3-hydroxybutyrate (3-OHB) inhibits lipolysis in healthy individuals. The current study aimed to test whether this feedback suppression of lipolysis by 3-OHB is disrupted in individuals with type 1 diabetes.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;We used a single-blind, randomised, crossover design to study ten men diagnosed with type 1 diabetes and ten healthy control participants. Eligibility criteria were male sex, age ≥18 years, BMI of 19–26 kg/m&lt;sup&gt;2&lt;/sup&gt; and no severe comorbidities/diseases. Following an overnight fast, each participant received two 3 h i.v. infusions: (i) sodium-&lt;span&gt;d/l&lt;/span&gt;-3-OHB and (ii) iso-osmolar saline (NaCl), separated by a 1 h washout period. The order of the two interventions was assigned by randomisation for each participant. Participants were blinded to the allocation throughout the study day, but investigators were aware of the assigned intervention order. We evaluated the lipolytic rate and glucose turnover using [9,10-&lt;sup&gt;3&lt;/sup&gt;H]palmitate and [3-&lt;sup&gt;3&lt;/sup&gt;H]glucose tracers. Additionally, adipose tissue signalling was quantified using western blotting techniques in subcutaneous abdominal adipose tissue biopsies. The primary endpoint measure was palmitate flux (lipolytic rate).&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;During the infusion of 3-OHB, the &lt;span&gt;d/l&lt;/span&gt;-3-OHB blood concentrations increased to 3.3 ± 0.7 mmol/l in participants with type 1 diabetes compared with 2.9 ± 0.5 mmol/l in control participants (&lt;i&gt;p&lt;/i&gt;=0.03). The infusion effectively suppressed the lipolytic rates by more than 50% (&lt;i&gt;p&lt;/i&gt;&lt;0.001) and reduced circulating NEFA by approximately 0.5 mmol/l (&lt;i&gt;p&lt;/i&gt;&lt;0.001) compared with NaCl in both participants with type 1 diabetes and control participants. In adipose tissue, 3-OHB reduced protein kinase A phosphorylation of perilipin (&lt;i&gt;p&lt;/i&gt;&lt;0.001) and hormone-sensitive lipase phosphorylation at Ser660 (&lt;i&gt;p&lt;/i&gt;&lt;0.001) and Ser563 (&lt;i&gt;p&lt;/i&gt;&lt;0.01) similarly in participants with type 1 diabetes and control participants. Indices of glucose metabolism remained unaffected throughout in both groups.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;Our findings indicate that, in individuals with type 1 diabetes, the suppression of lipolysis, blood NEFA concentrations and adipose tissue signalling activity in response to 3-OHB remains intact compared with healthy control participants. These findings imply that derailment of receptor signalling by 3-OHB is unlikely to be involved in the development of diabetic ketoacidosis.&lt;/p&gt;&lt;p&gt;Trial registration: ClinicalTrials.gov NCT04656236&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Fun","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"74 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819429","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":"Cardiac remodelling, recognition memory deficits and accelerated ageing in a rat model of gestational diabetes","authors":"Sathya Velmurugan, Vivek K. Pandey, Nirmal Verma, Deepak Kotiya, Florin Despa, Sanda Despa","doi":"10.1007/s00125-025-06421-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06421-7","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Women with prior gestational diabetes mellitus (GDM) have higher incidence of age-associated diseases, including type 2 diabetes, CVD and cognitive impairment. Human studies cannot readily determine whether GDM causes these conditions or the underlying mechanisms. Here we used a well-validated rat model of GDM to address these questions.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Rats with beta cell-specific expression of human amylin, a pancreatic hormone, were used as a GDM model. Five-month-old female rats were randomly assigned to no-pregnancy, one-pregnancy and two-pregnancies experimental groups. GTTs and transthoracic echocardiography were performed at baseline and during the postpartum period. At 18 months of age, the novel object recognition test was administered, followed by euthanasia and organ collection.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>All female rats developed glucose intolerance and showed cardiac remodelling and impaired left ventricular relaxation with ageing. Glucose intolerance was exacerbated in rats with prior GDM pregnancies compared with nulliparous rats, with significant differences starting at 9 months of age. However, blood glucose levels were comparable in the three groups during the course of the study. Rats with two GDM-complicated pregnancies had increased left ventricular mass compared with the other groups following the second pregnancy and until the end of the study. At 18 months of age, rats with prior GDM pregnancies presented aggravated demyelination, particularly in the hippocampus and mid-brain region, oxidative stress and neuroinflammation, and had a lower recognition index in the novel object recognition test compared with nulliparous rats. Higher parity exacerbated these effects. Shorter telomeres and reduced mitochondrial DNA content, two hallmarks of biological ageing, were found in the brain, heart and pancreas of rats with prior GDM.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>These findings support the concept that GDM is a sex-specific risk factor for ageing-related diseases, and point to accelerated cellular ageing as a contributing mechanism.</p><h3 data-test=\"abstract-sub-heading\">Data availability</h3><p>Cardiac echocardiography and GTT data are available at Dataverse under the identifier https://doi.org/10.7910/DVN/R2HITG</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"84 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782417","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 effect of once-weekly insulin icodec vs once-daily basal insulin on physical activity-attributed hypoglycaemia in type 2 diabetes: a post hoc analysis of ONWARDS 1–5","authors":"Michael C. Riddell, Simon Heller, Lisbeth Carstensen, Thaís M. Pagliaro Rocha, Sara Kehlet Watt, Vincent C. Woo","doi":"10.1007/s00125-025-06414-6","DOIUrl":"https://doi.org/10.1007/s00125-025-06414-6","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Physical activity increases the risk of hypoglycaemia in individuals with type 2 diabetes when basal or basal-bolus insulin therapy is administered. Once-weekly basal insulins may elevate the risk of physical activity-attributed hypoglycaemia compared with other basal insulins because the administered levels cannot be reduced in anticipation of increased physical activity. This post hoc analysis of five separate randomised trials (ONWARDS 1–5) aimed to examine physical activity-attributed hypoglycaemic episodes in adults with type 2 diabetes receiving either once-weekly basal insulin icodec (herein referred to as ‘icodec’) or once-daily basal insulins.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;The ONWARDS 1–5 Phase 3a randomised controlled trials compared the efficacy and safety of once-weekly basal icodec vs once-daily basal insulin in insulin-naive (ONWARDS 1, 3 and 5) and insulin-experienced (ONWARDS 2 and 4) adults with type 2 diabetes. Participants self-monitored their blood glucose levels using a blood glucose meter and a digital diary. In each trial, suspected hypoglycaemia symptoms triggered additional self-measured blood glucose readings, and values indicative of hypoglycaemia were recorded in the participants’ digital diary. Participants who experienced hypoglycaemic episodes were instructed to note any relation of each episode to physical activity. Hypoglycaemic episodes were classified as alert value (level 1: blood glucose &lt;3.9 but ≥3.0 mmol/l), clinically significant (level 2: blood glucose &lt;3.0 mmol/l) or severe (level 3: cognitive impairment requiring external assistance). The proportions of hypoglycaemic episodes that were attributed to physical activity and the ORs of having a physical activity-attributed hypoglycaemic episode were calculated for the two basal insulin types (once-weekly vs once-daily) for each of the five trials.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Across all trials, there were no consistent differences between icodec and the once-daily insulin comparators in the proportions of hypoglycaemic episodes that were attributed to physical activity; these episodes were mainly alert value or clinically significant hypoglycaemic episodes. In both insulin-naive and insulin-experienced participants, the incidence of physical activity-attributed clinically significant or severe hypoglycaemic episodes was consistently ≤3.0% in ONWARDS 1, 2, 3 and 5. In ONWARDS 4, the incidence of physical activity-attributed hypoglycaemic episodes was numerically higher in both treatment groups (18.6% [icodec] vs 17.9% [insulin glargine U100]), which was expected given the basal-bolus insulin regimen. Across all trials, there were no statistically significant differences in the odds of experiencing a physical activity-attributed clinically significant or severe hypoglycaemic episode with icodec vs once-daily insulin comparators. The frequency of","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"108 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782419","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":"Clinical use of polygenic scores in type 2 diabetes: challenges and possibilities","authors":"Rashmi B. Prasad, Liisa Hakaste, Tiinamaija Tuomi","doi":"10.1007/s00125-025-06419-1","DOIUrl":"https://doi.org/10.1007/s00125-025-06419-1","url":null,"abstract":"<p>Resulting from a combination of genetic and environmental factors, type 2 diabetes is highly heterogeneous in manifestation and disease progression, with the only common feature being chronic hyperglycaemia. In spite of vigorous efforts to elucidate the pathogenetic origins and natural course of the disease, there is still a lack of biomarkers and tools for prevention, disease stratification and treatment. Genome-wide association studies have reported over 1200 variants associated with type 2 diabetes, and the decreased cost of generating genetic data has facilitated the development of polygenic scores for estimating an individual’s genetic disease risk based on combining effects from most—or all—genetic variants. In this review, we summarise the current knowledge on type 2 diabetes-related polygenic scores in different ancestries and outline their possible clinical role. We explore the potential applicability of type 2 diabetes polygenic scores to quantify genetic liability for prediction, screening and risk stratification. Given that most genetic risk loci are determined from populations of European origin while other ancestries are under-represented, we also discuss the challenges around their global applicability. To date, the potential for clinical utility of polygenic scores for type 2 diabetes is limited, with such scores outperformed by clinical measures. In the future, rather than predicting risk of type 2 diabetes, the value of polygenic scores may be in stratification of the severity of disease (risk for comorbidities) and treatment response, in addition to aiding in dissecting the pathophysiological mechanisms involved.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"34 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782418","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":"Parent-of-origin effects in the life-course evolution of cardiometabolic traits","authors":"Rucha Wagh, Gad Hatem, Jonas Andersson, Pooja Kunte, Souvik Bandyopadhyay, Chittaranjan S. Yajnik, Rashmi B. Prasad","doi":"10.1007/s00125-025-06396-5","DOIUrl":"https://doi.org/10.1007/s00125-025-06396-5","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Cardiometabolic traits are heritable, and some display parent-of-origin effects, which indicates preferential inheritance from one parent or parental bias. Most studies of these phenomena have focused on adult populations. We aimed to investigate the heritability and parent-of-origin effects on cardiometabolic traits in a birth cohort with serial measurements to determine whether these patterns emerged early in life.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;The Pune Maternal Nutrition Study comprises a birth cohort in which offspring and parents were studied from birth and followed up for 24 years. We investigated parent-of-origin effects on cardiometabolic traits cross-sectionally at available timepoints using linear regression, and longitudinally across the life course using mixed-effect regression. Maternal and paternal effects on offspring phenotype were modelled after adjusting for age, sex and BMI. Parent-of-origin effects were calculated based on the difference between maternal and paternal effects. We also investigated these effects in another birth cohort, that of the Pune Children’s Study. Genetic parent-of-origin effects were assessed using generalised estimating equations after taking the parental origin of the alleles into account.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Birthweight showed a maternal parent-of-origin effect. At 24 years, maternal bias was seen for some obesity-related traits for daughters, while paternal bias was seen for WHR in sons. A shift from paternal bias at 6 years to maternal bias at 24 years for the skinfold thickness was observed in daughters. Fasting glucose and lipids showed maternal bias at 6, 12 and 24 years. For fasting insulin and HOMA2-S, a negative maternal effect at 6 years transitioned to a positive one at 12 years. For HOMA2-B, a paternal effect at 6 years transitioned to a maternal one at 12 years, and this remained so at 24 years. Some of these findings were also observed in the cohort from the Pune Children’s Study. Longitudinal modelling revealed stronger paternal effects over time for fasting insulin and HOMA indices but maternal effects for glucose and lipids, reflecting their cumulative effect over time. Genetic variants at the &lt;i&gt;KCNQ1&lt;/i&gt; locus showed a maternal parent-of-origin effect on birthweight, on HOMA2-B at 12 years, and on lipids at 6 and 12 years.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;Our study provides proof of concept of the existence of parent-of-origin effects on cardiometabolic traits from birth, through childhood and puberty, until adult age. Our results indicate a predominantly maternal influence on intrauterine, pubertal and reproductive-age metabolism in the offspring. While the longitudinal analysis indicated a maternal bias for the macronutrients (glucose and lipids), and a paternal bias for glucose–insulin metabolism, the cross-sectional analy","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"41 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766795","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}