Diabetologia最新文献

{"title":"Type 1 diabetes prediction in autoantibody-positive individuals: performance, time and money matter","authors":"Lauric A. Ferrat, Erin L. Templeman, Andrea K. Steck, Hemang M. Parikh, Lu You, Suna Onengut-Gumuscu, Peter A. Gottlieb, Taylor M. Triolo, Stephen S. Rich, Jeffrey Krischer, R. Brett McQueen, Richard A. Oram, Maria J. Redondo","doi":"10.1007/s00125-025-06434-2","DOIUrl":"https://doi.org/10.1007/s00125-025-06434-2","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Efficient prediction of clinical type 1 diabetes is important for risk stratification and monitoring of autoantibody-positive individuals. In this study, we compared type 1 diabetes predictive models for predictive performance, cost and participant time needed for testing.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We developed 1943 predictive models using a Cox model based on a type 1 diabetes genetic risk score (GRS2), autoantibody count and types, BMI, age, self-reported gender and OGTT-derived glucose and C-peptide measures. We trained and validated the models using halves of a dataset comprising autoantibody-positive first-degree relatives of individuals with type 1 diabetes (<i>n</i>=3967, 49% female, 14.9 ± 12.1 years of age) from the TrialNet Pathway to Prevention study. The median duration of follow-up was 4.7 years (IQR 2.0–8.1), and 1311 participants developed clinical type 1 diabetes. Models were compared for predictive performances, estimated cost and participant time.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Models that included metabolic measures had best performance, with most exhibiting small performance differences (less than 3% and <i>p</i>&gt;0.05). However, the cost and participant time associated with measuring metabolic variables ranged between US$56 and US$293 and 10–165 min, respectively. The predictive model performance had temporal variability, with the highest GRS2 influence and discriminative power being exhibited in the earliest preclinical stages. OGTT-derived metabolic measures had a similar performance to HbA_1c- or Index₆₀-derived models, with an important difference in cost and participant time.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Cost–performance model analyses identified trade-offs between cost and performance models, and identified cost-minimising options to tailor risk-screening strategies.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"50 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931027","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 in tight range and time in range for predicting the achievement of typical glucose management indicator and HbA1c targets.","authors":"Seohyun Kim,Sang Ho Park,Jin A Lee,So Hyun Cho,Rosa Oh,Ji Yoon Kim,You-Bin Lee,Gyuri Kim,Kyu Yeon Hur,Jae Hyeon Kim,Sang-Man Jin","doi":"10.1007/s00125-025-06442-2","DOIUrl":"https://doi.org/10.1007/s00125-025-06442-2","url":null,"abstract":"AIMS/HYPOTHESISThis study aimed to compare the ability of time in tight range (TITR) and time in range (TIR) to predict the achievement of typical glucose management indicator (GMI) and HbA1c targets.METHODSThis cross-sectional analysis included 773 adults with diabetes receiving insulin therapy who visited Samsung Medical Center between June 2019 and December 2023 and wore a Dexcom G6 or FreeStyle Libre continuous glucose monitor for at least 90 days (sensor wear time, ≥70%). A receiver operating characteristic analysis was used to compare the ability of TITR and TIR to predict GMI and HbA1c targets.RESULTSTITR had significantly greater AUC values than TIR for predicting GMIs of <53 mmol/mol (7.0%) and <48 mmol/mol (6.5%) among participants using a Dexcom G6 or FreeStyle Libre continuous glucose monitor. TITR also had significantly greater AUC values than TIR for predicting HbA1c levels of <53 mmol/mol (7.0%) (95% CI for difference: 0.006, 0.03) and <48 mmol/mol (6.5%) (95% CI for difference: 0.001, 0.03) among participants using the FreeStyle Libre. In the HbA1c range of 48-53 mmol/mol (6.5-7.0%), TIR exhibited broader variations than TITR across CV groups. The modifying effect of CV on the association between TITR and GMI or HbA1c was minimised around a GMI and HbA1c level of 53 mmol/mol (7.0%).CONCLUSIONS/INTERPRETATIONTITR might be a more useful indicator than TIR of the achievement of typical GMI and HbA1c targets among adults with diabetes on insulin therapy.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"65 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914921","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":"Correction: Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","authors":"Ildiko Lingvay, Malik Benamar, Liming Chen, Ariel Fu, Esteban Jódar, Tomoyuki Nishida, Jean-Pierre Riveline, Daisuke Yabe, Thomas Zueger, Rosângela Réa","doi":"10.1007/s00125-025-06435-1","DOIUrl":"https://doi.org/10.1007/s00125-025-06435-1","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"6 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910146","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":"Up Front","authors":"","doi":"10.1007/s00125-025-06444-0","DOIUrl":"https://doi.org/10.1007/s00125-025-06444-0","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"139 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910209","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":"Treatment discontinuation among users of GLP-1 receptor agonists and SGLT2 inhibitors in a national population of individuals with type 2 diabetes","authors":"Carl-Emil Lim, Björn Pasternak, Björn Eliasson, Peter Ueda","doi":"10.1007/s00125-025-06439-x","DOIUrl":"https://doi.org/10.1007/s00125-025-06439-x","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Our aim was to assess treatment discontinuation, reinitiation and switching between drugs within the same drug class for glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors in individuals with type 2 diabetes.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;We used data from nationwide registers in Sweden to perform separate analyses for all patients with type 2 diabetes who filled a first prescription of a GLP-1 receptor agonist or an SGLT2 inhibitor between 2017 and 2021. Patients were considered to be on treatment for the period during which prescriptions were refilled before the estimated end date of the most recent prescription, including a 90-day grace period, i.e. the time allowed between and after prescriptions before treatment is considered as discontinued. We used the Aalen–Johansen estimator to estimate cumulative incidences of discontinuation and reinitiation, and Fine–Gray sub-distribution hazard models to assess the association of clinical variables with the risk of discontinuation.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Among 73,895 new users of GLP-1 receptor agonists, the cumulative incidence of treatment discontinuation was 23.6% at 1 year and 38.5% at 3 years. Among patients who discontinued, the cumulative incidence of treatment reinitiation was 41.1% at 1 year and 57.4% at 3 years after discontinuation. Among 113,207 new users of SGLT2 inhibitors, the cumulative incidence of treatment discontinuation was 27.9% at 1 year and 45.9% at 3 years, with a cumulative incidence of reinitiation of 40.4% at 1 year and 55.7% at 3 years after discontinuation. When varying the grace period between 60 days and 365 days, treatment discontinuation rates at 3 years ranged from 23.3% to 43.6% among GLP-1 receptor agonist users and from 28.8% to 50.6% among SGLT2 inhibitor users. The proportion of patients who had ongoing treatment, regardless of previous discontinuation episodes, ranged between approximately 70% and 80% for both drugs during a 1–5 year period after treatment initiation across analyses using various grace periods. In terms of switching, 22.9% of the GLP-1 receptor agonist users and 2.1% of the SGLT2 inhibitor users switched between drugs within the same drug class. Patient characteristics associated with treatment discontinuation were similar for GLP-1 receptor agonists and SGLT2 inhibitors, although the association between higher BMI and a lower likelihood of treatment discontinuation was stronger for GLP-1 receptor agonists.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;Approximately half of type 2 diabetes patients who had started using GLP-1 receptor agonists or SGLT2 inhibitors had discontinued treatment within 5 years of follow-up. However, more than half of those who discontinued treatment subsequently reinitiated treatment, such that the proportion with ongoing","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"15 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901294","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":"Duration and type of statin use and long-term risk of type 2 diabetes among men and women with hypercholesterolaemia: findings from three prospective cohorts","authors":"Yiwen Zhang, Yanping Li, Yuxi Liu, Walter C. Willett, JoAnn E. Manson, Meir J. Stampfer, Frank B. Hu, Edward L. Giovannucci, Dong D. Wang","doi":"10.1007/s00125-025-06441-3","DOIUrl":"https://doi.org/10.1007/s00125-025-06441-3","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Findings from RCTs and observational studies indicate a positive association between statin use and risk of type 2 diabetes. Mendelian randomisation studies provide evidence to support that the effect is causal. However, little is known about the long-term effects, and data on different types of statins remain limited.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;We analysed participants with hypercholesterolaemia from the Nurses’ Health Study (NHS; 30,510 participants), the Nurses’ Health Study II (NHSII; 21,547 participants) and the Health Professionals Follow-Up Study (HPFS; 9934 participants) who were free of diabetes, CVD and cancer at baseline. Statin use was assessed every 2 years starting in 2000 in the NHS and the HPFS and in 1999 in the NHSII. Incident cases of type 2 diabetes were confirmed by a validated supplementary questionnaire until the end of follow-up (31 January 2023).&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;We documented 6762 incident type 2 diabetes cases during up to 23 years of follow-up. Compared with non-users, statin users had a significantly higher risk of type 2 diabetes after adjustment for BMI and other potential confounding variables (pooled HR 1.40; 95% CI 1.33, 1.48). Compared with non-use, durations of statin use of 1–5, 6–10, 11–15 and &gt;15 years were associated with HRs of 1.36 (95% CI 1.27, 1.44), 1.41 (95% CI 1.31, 1.52), 1.60 (95% CI 1.44, 1.78) and 1.76 (95% CI 1.50, 2.06), respectively; significant linear trends were observed when the comparison included non-users and within statin users only (both &lt;i&gt;p&lt;/i&gt;&lt;sub&gt;trend&lt;/sub&gt;&lt;0.001). Compared with non-users, the HRs for type 2 diabetes associated with 10 year use of specific types of statins were 1.99 (95% CI 1.45, 2.73) for rosuvastatin, 1.66 (95% CI 1.12, 2.47) for lovastatin, 1.62 (95% CI 1.39, 1.89) for atorvastatin, 1.44 (95% CI 1.06, 1.97) for pravastatin and 1.37 (95% CI 1.13, 1.66) for simvastatin. Use of a low-potency statin for 10 years was associated with a 34% higher risk of type 2 diabetes (HR 1.34; 95% CI 1.15, 1.56), while use of a high-potency statin for 10 years was associated with a 72% higher risk (HR 1.72; 95% CI 1.46, 2.04). The difference in the 10 year cumulative risk of type 2 diabetes comparing statin users vs non-users was most pronounced in participants with the least healthy lifestyles (4.5% vs 3.1%), while the smallest risk differential was observed among participants who adhered to the healthiest lifestyles (1.0% vs 0.4%).&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;The positive association between statin use and type 2 diabetes was more pronounced with a longer duration of use, and the association varied across different types of statins. Adopting and maintaining a healthy lifestyle can serve as a viable approach to diabetes prevention during statin treatment.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Graphical ","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"22 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901295","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":"Aetiology of type 2 diabetes: an experimental medicine odyssey","authors":"Roy Taylor","doi":"10.1007/s00125-025-06428-0","DOIUrl":"https://doi.org/10.1007/s00125-025-06428-0","url":null,"abstract":"<p>This review describes a prolonged research endeavour to test the twin cycle hypothesis that type 2 diabetes is caused by fat-induced dysfunction of the liver and pancreas, guided by the happenstance of clinical practice. Testing of the personal fat threshold hypothesis, that individuals exhibit different levels of tolerance to intra-organ fat accumulation, is also described. Both hypotheses predict that type 2 diabetes is potentially reversible by weight loss. The results of the Counterpoint study supported the twin cycle hypothesis, leading to a second study which determined that short-duration diabetes was more likely to remit following the 10–15 kg weight loss. It also confirmed that remission was durable over 6 months on an isoenergetic, normal diet. Subsequently, it was shown that weight loss caused an immediate decrease of pancreas fat only in people with type 2 diabetes and also that postprandial incretin spikes after bariatric surgery had no role in normalising fasting plasma glucose. DiRECT, a 2 year randomised controlled study, demonstrated clinical utility, observing functional beta cell capacity to return almost to normal over 12 months. A small group of participants regained weight and redeveloped type 2 diabetes, allowing observation that the underlying pathophysiological mechanisms during onset of diabetes were as postulated by the twin cycle hypothesis. Major clinical benefit was demonstrated after a further 3 year follow-up in routine care, halving the incidence of serious adverse effect compared with the standard treatment control group. In answer to the question of whether individuals have a personal fat threshold for tolerance of fat, stepwise weight loss in people with type 2 diabetes and BMI in the range 21–27 kg/m² resulted in remission in 70%, with a wide range of fat thresholds. Type 2 diabetes can be regarded as a condition of homogenous aetiology in genetically heterogenous individuals.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"97 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901293","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":"Eukaryotic translation initiation factor 2A protects pancreatic beta cells during endoplasmic reticulum stress while rescuing global translation inhibition","authors":"Evgeniy Panzhinskiy, Søs Skovsø, Haoning Howard Cen, Amanda Rahardjo, Jiashuo Aaron Zhang, Kwan Yi Chu, Kate MacDonald, Galina Soukhatcheva, Derek A. Dionne, Luisa K. Hallmaier-Wacker, Jennifer S. Wildi, Stephanie Marcil, Nilou Noursadeghi, Farnaz Taghizadeh, C. Bruce Verchere, Eric Jan, James D. Johnson","doi":"10.1007/s00125-025-06431-5","DOIUrl":"https://doi.org/10.1007/s00125-025-06431-5","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;The endoplasmic reticulum (ER) stress-induced unfolded protein response helps determine beta cell survival rate in diabetes. The alternative eukaryotic translation initiation factor 2A (EIF2A) has been proposed to mediate translation initiation independent of the α subunit of EIF2 (EIF2S1) during cellular stress, but its role in beta cells has not been comprehensively examined.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;For in vitro experiments, we used MIN6 cells, primary mouse pancreatic islets, and human islets obtained under informed consent. Thapsigargin (1 µmol/l) or palmitate complexed with BSA (0.5 mmol/l) was used to induce ER stress. Transient transfection and lentiviral infection were used for transgene delivery. For in vivo experiments, adeno-associated viral particles expressing EIF2A or GFP under the control of a rat insulin promoter were delivered via intraductal injection to 6-week-old female Akita mice randomised into three groups (two cohorts, &lt;i&gt;n&lt;/i&gt;=10–11). Tail blood was collected for blood glucose measurements for single time points as well as during glucose and insulin tolerance tests.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;EIF2A protein abundance and specificity was high in human and mouse islets relative to other tissues. We used STRING and AlphaFold pulldown to predict interacting proteins and binding partners, verifying EIF1AX with co-immunoprecipitation. Both thapsigargin and palmitate significantly increased &lt;i&gt;EIF2A&lt;/i&gt; mRNA and EIF2A protein levels in MIN6 cells, mouse islets and human islets. Knockdowns of EIF2A, the related factor EIF2D or both EIF2A and EIF2D were not sufficient to cause apoptosis. On the other hand, transient or stable EIF2A overexpression protected MIN6 cells, primary mouse islets and human islets from ER stress-induced, caspase-3-dependent apoptosis. Mechanistically, EIF2A overexpression decreased endoplasmic reticulum to nucleus signalling 1 (ERN1, also known as inositol-requiring enzyme 1 α or IRE1α) expression in thapsigargin-treated MIN6 cells or human islets. In vivo, beta cell-specific EIF2A viral overexpression reduced ER stress and improved insulin secretion and glucose tolerance in &lt;i&gt;Ins2&lt;/i&gt;&lt;sup&gt;Akita/WT&lt;/sup&gt; mice. EIF2A overexpression significantly increased expression of genes involved in mRNA translation and reduced expression of pro-apoptotic genes (e.g. &lt;i&gt;Aldh1a3&lt;/i&gt;). Proteomic analysis of EIF2A-overexpressing human islets revealed significant changes in pathways associated with ribosomes and protein processing in ER. Remarkably, the decrease in global protein synthesis during unfolded protein response was prevented by EIF2A, despite ER stress-induced EIF2S1 phosphorylation. The protective effects of EIF2A were additive to those of ISRIB, a drug that counteracts the effects of EIF2S1 phosphorylation. Cells overexpressing EIF2A showed higher expression of translation factor EIF2B5, which ","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"167 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890124","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":"Insulin resistance in type 1 diabetes is a key modulator of platelet hyperreactivity","authors":"Rebecca C. Sagar, Daisie M. Yates, Sam M. Pearson, Noppadol Kietsiriroje, Matthew S. Hindle, Lih T. Cheah, Beth A. Webb, Ramzi A. Ajjan, Khalid M. Naseem","doi":"10.1007/s00125-025-06429-z","DOIUrl":"https://doi.org/10.1007/s00125-025-06429-z","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Individuals with type 1 diabetes are at increased cardiovascular risk, particularly in the presence of insulin resistance. A prothrombotic environment is believed to contribute to this risk but thrombotic pathways in type 1 diabetes are only partially understood and the role of platelets is incompletely studied. We hypothesised that platelets from individuals with type 1 diabetes exhibit platelet hyperactivity due to both increased propensity for activation and diminished sensitivity to inhibition, with an amplified maladaptive phenotype in those with insulin resistance.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;Blood samples were obtained from individuals with type 1 diabetes enrolled on the ‘Double diabEtes and adVErse cLinical Outcome: identification of mechanistic Pathways’ (DEVELOP) study with insulin resistance assessed as estimated glucose disposal rate (eGDR), whereby eGDR &gt;8 or &lt;6 mg kg&lt;sup&gt;−1&lt;/sup&gt; min&lt;sup&gt;−1&lt;/sup&gt; indicates normal insulin sensitivity or advanced insulin resistance, respectively. Platelet function was analysed using whole blood multiparameter flow cytometry to simultaneously measure three distinct markers of activation, including integrin α&lt;sub&gt;IIb&lt;/sub&gt;β&lt;sub&gt;3&lt;/sub&gt; (PAC-1 binding), P-selectin (CD62P) and phosphatidylserine (PS) (Annexin V). Both activation and inhibition responses of the platelets were investigated, which were subjected to the machine learning tool Full Annotation Shape-constrained Trees (FAUST) to characterise platelet subpopulations.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;A total of 32 individuals with type 1 diabetes were studied (median age [range] of 24 [18–34] years, 59% male, diabetes duration [mean ± SD] of 14.0 ± 6.3 years and HbA&lt;sub&gt;1c&lt;/sub&gt; of 65.3 ± 14.0 mmol/mol [8.1%]). An increased basal expression, measured as mean fluorescence intensity, of all three platelet activation markers was detected in the type 1 diabetes group compared with healthy control participants (CD62P expression 521 ± 246 vs 335 ± 67; &lt;i&gt;p&lt;/i&gt;&lt;0.001, PAC-1 370 ± 165 vs 231 ± 88; &lt;i&gt;p&lt;/i&gt;=0.011 and PS 869 ± 762 vs 294 ± 109; &lt;i&gt;p&lt;/i&gt;=0.001). Following platelet stimulation, an enhanced activation of these markers was found in the type 1 diabetes group. Within the type 1 diabetes group, those with advanced insulin resistance (eGDR&lt;6 mg kg&lt;sup&gt;−1&lt;/sup&gt; min&lt;sup&gt;−1&lt;/sup&gt;) showed increased platelet activation compared with individuals with normal insulin sensitivity (eGDR&gt;8 mg kg&lt;sup&gt;−1&lt;/sup&gt; min&lt;sup&gt;−1&lt;/sup&gt;) with single agonist stimulation CD62P expression (29,167 ± 2177 vs 22,829 ± 2535, &lt;i&gt;p&lt;/i&gt;&lt;0.001 and PAC-1 19,339 ± 11,749 and 5187 ± 2872, &lt;i&gt;p&lt;/i&gt;=0.02). Moreover, individuals with type 1 diabetes showed reduced sensitivity to platelet inhibition by prostacyclin (PGI&lt;sub&gt;2&lt;/sub&gt;) compared with control participants. Stratification of individuals with type 1 diabetes by insulin resistance demonstrated that in the","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"135 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890101","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":"Relationship between sRAGE and obesity in individuals with type 1 diabetes during a median follow-up of 6.3 years","authors":"Krishna Adeshara, Erika B. Parente, Valma Harjutsalo, Markku Lehto, Niina Sandholm, Per-Henrik Groop","doi":"10.1007/s00125-025-06440-4","DOIUrl":"https://doi.org/10.1007/s00125-025-06440-4","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Soluble receptor for advanced glycation end products (sRAGE) has been inversely linked to obesity, which is defined by excess of total body fat. However, body fat accumulation is also relevant for health. In this study, we investigated associations between sRAGE and obesity in individuals with type 1 diabetes over 6.3 years of follow-up.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>The study included 3886 adults with type 1 diabetes from the FinnDiane study. Serum sRAGE concentrations were determined by ELISA. Central obesity was defined on the basis of waist/height ratio (WHtR), and general obesity on the basis of BMI. The Kruskal–Wallis test was used to assess the differences in baseline BMI, WHtR and sRAGE concentrations, comparing the groups stratified by albuminuria status. Changes in BMI and WHtR were calculated over time and Wilcoxon rank test was used for comparisons. Linear regression, adjusted for sex, age, albuminuria and HbA_1c, was used for assessing the association of sRAGE with obesity measures at baseline, and with changes over time.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Over a median follow-up of 6.3 years, BMI changed by a median Δ of 0.76 kg/m² (IQR −0.39 to 2.07; <i>p</i>&lt;0.001) and WHtR by a median Δ of 0.019 (IQR −0.007 to 0.05; <i>p</i>&lt;0.001). The change in BMI was observed in 67% of the individuals, and WHtR in 68% of them. Baseline sRAGE was inversely associated with BMI (<i>r</i>²=0.07, β −0.174; <i>p</i>&lt;0.001) and WHtR (<i>r</i>²=0.16, β −0.179; <i>p</i>&lt;0.001) in the overall cohort. These relationships remained consistent across subgroups stratified by albuminuria status, including no, moderate and severe albuminuria (all <i>p</i>&lt;0.001). However, sRAGE was not associated with changes in BMI or WHtR over time.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>sRAGE is inversely associated with both general and central obesity, as represented by BMI and WHtR, independent of kidney disease, suggesting sRAGE is a biomarker of obesity. However, sRAGE is not associated with the changes in BMI and WHtR over a 6.3 year follow-up. Future research with longer follow-up is merited to understand how sRAGE correlates with body fat accumulation.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"7 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890119","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}