Diabetologia最新文献

{"title":"LASP1 mediates ADAM17 upregulation in high glucose to promote fibrosis in diabetic kidneys.","authors":"Jackie Trink, Bo Gao, Renzhong Li, Jaina H Patel, Urooj Bajwa, Alma Zernecke, Elke Butt, Joan C Krepinsky","doi":"10.1007/s00125-025-06662-6","DOIUrl":"10.1007/s00125-025-06662-6","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Diabetic kidney disease (DKD), a prevalent complication of diabetes, is the leading cause of chronic kidney disease globally. The current standard of care cannot halt disease progression and thus new therapeutic targets are needed. We previously showed that the metalloprotease ADAM17 mediates the profibrotic response to high glucose in kidney mesangial cells. Its upregulation in high glucose conditions augments its profibrotic effects. Here we investigate regulation of the Adam17 promoter region -2304/-1567, previously shown to be glucose responsive, for which regulatory factors have not yet been identified.</p><p><strong>Methods: </strong>Adam17 promoter regulation, cell surface translocation and activation were assessed in primary rat mesangial cells using standard molecular biology techniques. Type 1 diabetes was induced in mice using streptozocin and kidney function and development of fibrosis were assessed after 24 weeks. Human and mouse kidneys were immunostained for LASP1.</p><p><strong>Results: </strong>In rat mesangial cells, the LIM and SH3 protein 1 (LASP1) was identified as a regulator of the Adam17 promoter in response to high glucose by mass spectrometry of nuclear lysate proteins binding to the -2304/-1567 promoter region. Knockdown of LASP1 prevented glucose-induced Adam17 promoter activation and transcript and protein upregulation. LASP1 nuclear localisation and regulation of Adam17 promoter activity in high glucose required phosphorylation of LASP1 on S146 by protein kinase A, but not protein kinase G, and Y171 phosphorylation by Src kinase. LASP1 also regulated glucose-induced ADAM17 cell surface localisation and activation, dependent on its phosphorylation by Src and interaction with focal adhesion kinase. Profibrotic responses to glucose were inhibited by LASP1 downregulation. In vivo, LASP1 expression was increased in the kidneys of type 1 diabetic mice and in kidneys of patients with DKD. Mice with Lasp1 knockout showed attenuated development of DKD.</p><p><strong>Conclusions/interpretation: </strong>LASP1 regulates the synthesis and activation of ADAM17 in mesangial cells and is required for the profibrotic response to high glucose. Its deletion protects against DKD in mice. Targeting LASP1 may have therapeutic value as an indirect method of ADAM17 inhibition to inhibit fibrosis in DKD.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1703-1719"},"PeriodicalIF":10.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131411","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":"Canagliflozin attenuates CMR-quantified myocardial fibrosis in individuals with type 2 diabetes mellitus at high cardiovascular risk: a randomised open-label controlled trial.","authors":"Hongmei Yan, Jiaojiao Liu, Zhitian Zhang, Shuangshuang Chen, Xinxia Chang, Hang Jin, Xiaoying Li, Yinyin Chen, Ying Chen, Mengsu Zeng","doi":"10.1007/s00125-026-06682-w","DOIUrl":"10.1007/s00125-026-06682-w","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Aims/hypothesis: &lt;/strong&gt;We aimed to investigate canagliflozin's effects on myocardial fibrosis, cardiac structure and function, and microcirculation in high-cardiovascular-risk type 2 diabetes mellitus through cardiac magnetic resonance (CMR) quantification, while investigating the cardiovascular protective mechanisms of sodium-glucose cotransporter 2 (SGLT2) inhibitors.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This open-label parallel RCT recruited 45 high-risk participants (18-75 years) with type 2 diabetes (HbA&lt;sub&gt;1c&lt;/sub&gt; 53.0-91.3 mmol/mol [7.0-10.5%]) and left ventricular ejection fraction (LVEF) &gt;50% from the Endocrinology Outpatient Clinic of Zhongshan Hospital, Fudan University (August 2022 to November 2024). Participants were 1:1 randomised via a computer-generated sequence through the centralised iClinicalStation system (allocation concealed, performed by independent personnel not involved in outcome assessment). They received canagliflozin 100 mg/day (n=23) or sitagliptin 100 mg/day (n=22) for 26 weeks. Consistent with the open-label design, participants and care providers were aware of treatment assignments; however, outcome assessors (radiologists, sonographers) and data analysts remained blinded to group allocation to minimise bias. The primary endpoint was CMR-quantified extracellular volume (ECV) change. Secondary outcomes included ventricular structure and function parameters, for example, left ventricular end-diastolic volume, left ventricular end-diastolic diameter, LVEF, etc. RESULTS: Among 67 individuals screened, 45 completed the intention-to-treat analysis (age 60.4 ± 9.7 years, BMI 26.4 ± 2.6 kg/m&lt;sup&gt;2&lt;/sup&gt;, HbA&lt;sub&gt;1c&lt;/sub&gt; 63.0 ± 8.7 mmol/mol [7.9 ± 0.8%]). At 26 weeks, compared with sitagliptin, canagliflozin significantly reduced the primary outcome of ECV (adjusted mean difference [AMD]: -3.67%; 95% CI -5.33, -2.01; p&lt;0.001). Significant improvements were also observed in cardiac structure, including left ventricular end-diastolic volume (AMD: -20.72 ml; 95% CI -36.30, -5.14; p=0.010) and echocardiography-derived end-diastolic diameter (AMD: -2.82 mm; 95% CI -4.95, -0.70; p=0.010). Both groups showed comparable reductions in HbA&lt;sub&gt;1c&lt;/sub&gt; (both Δ 0.7%, inter-group p=0.972).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions/interpretation: &lt;/strong&gt;This study demonstrates that 26 weeks of canagliflozin significantly reduces myocardial fibrosis, as assessed by CMR-derived ECV, in individuals with type 2 diabetes at high cardiovascular risk, providing imaging evidence for SGLT2 inhibitor cardiovascular protection mechanisms.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Trial registration: &lt;/strong&gt;ClinicalTrials.gov NCT05367063 FUNDING: This study was financially supported by the National Key Research and Development programme (2023YFA1802000), the National Natural Science Foundation of China (Youth Fund 82200909), the Young and Middle-aged Diabetes project from the Bethune Foundation (Z04JKM2022E002), the Joint Research Development project between Shenkang and Un","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1532-1544"},"PeriodicalIF":10.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147282802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges in and opportunities for individualising diabetes technology: a position statement by the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) Diabetes Technology Working Group.","authors":"Daniela Bruttomesso, John R Petrie, Mark Evans, G Alexander Fleming, Helene Hanaire, Reinhard W Holl, Jennifer L Sherr, Richard M Bergenstal, Lutz Heinemann, Anne L Peters","doi":"10.1007/s00125-025-06651-9","DOIUrl":"10.1007/s00125-025-06651-9","url":null,"abstract":"<p><p>From fingerstick blood glucose monitoring and mechanical insulin pens in the 1970s to modern automated insulin delivery systems, rapidly progressing advances in diabetes technology are transforming management options for people with diabetes, particularly those with type 1 diabetes but also, increasingly, people with type 2 diabetes. However, access to life-changing diabetes technologies is neither uniform nor universally covered, and there is no one size fits all approach. In this position statement, we emphasise to healthcare professionals the importance of supporting individuals with diabetes to access and use the right diabetes technology according to personal needs, capabilities and preferences. In doing so, we highlight the equal importance of avoiding disparities in the provision of diabetes technology by challenging preconceived barriers, which can be overcome with education and determination. We also make a series of suggestions for action to advance the more widespread adoption of diabetes technology while minimising the 'digital divide'.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1393-1412"},"PeriodicalIF":10.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thromboxane signalling links immune activation to enhanced glucose uptake in skeletal muscle.","authors":"Ahmed M Abdelmoez, Maxence Jollet, Xue Yu, David Rizo-Roca, Alesandra A Marica, Joaquin Ortiz de Zevallos, Lucile Dollet, Melissa L Borg, Marie Björnholm, Antonio Checa, Tommy Olsson, Julia Otten, Juleen R Zierath, Anna Krook, Thue W Schwartz, Alexander V Chibalin, Nicolas J Pillon","doi":"10.1007/s00125-026-06684-8","DOIUrl":"10.1007/s00125-026-06684-8","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Exercise elicits a spectrum of metabolic and inflammatory responses that are crucial for skeletal muscle adaptation and overall health, particularly in the context of metabolic diseases, yet the contribution of prostanoid signalling to these processes remains unclear. We hypothesised that exercise-induced thromboxane production enhances skeletal muscle glucose uptake and improves whole-body glucose control.</p><p><strong>Methods: </strong>Plasma prostanoids were quantified in men and women with normal glucose tolerance or type 2 diabetes before, immediately after and 3 h after a single bout of exercise. Cyclooxygenase (COX-2) transcript levels were evaluated in human skeletal muscle, whole blood, peripheral blood mononuclear cells and skeletal muscle-resident immune cells. Metabolic and transcriptomic effects of thromboxane receptor activation were analysed in mouse C2C12, rat L6 and human primary skeletal muscle cells. Glucose tolerance in vivo was assessed following i.p. administration of the thromboxane receptor agonist I-BOP in male and female mice. Tissue-specific glucose uptake was quantified by measuring radiolabelled 2-deoxyglucose incorporation during an IVGTT.</p><p><strong>Results: </strong>Acute exercise increased plasma thromboxane B₂ concentrations and skeletal muscle mRNA levels of PTGS2 (encoding COX-2) selectively in monocyte/macrophage populations. In skeletal muscle cells, the thromboxane receptor agonist I-BOP increased glucose uptake in a dose-dependent manner up to 2.5-fold within 4 h and enhanced glycogen synthesis by 430%. Transcriptomic and signalling analysis revealed activation of protein kinase A and cytoskeletal remodelling pathways linked to GLUT4 trafficking. In vivo, I-BOP improved glucose tolerance in male mice in a dose-dependent manner, without altering insulin levels. Thromboxane receptor stimulation increased glucose uptake in extensor digitorum longus muscle by 43%. Importantly, thromboxane receptor activation preserved its glucose-lowering efficacy in diet-induced obese male mice.</p><p><strong>Conclusions/interpretation: </strong>Exercise induces skeletal muscle-derived thromboxane production through macrophage-specific COX-2 activation. Thromboxane receptor stimulation enhances glucose uptake and glycogen storage via cytoskeletal remodelling, partially mimicking the acute exercise transcriptomic response. In vivo, thromboxane receptor activation improves glucose tolerance and skeletal muscle glucose uptake, with preserved efficacy in obesity. These findings identify thromboxane signalling as a previously unrecognised immunometabolic axis linking inflammation to glucose regulation and highlight the thromboxane receptor as a potential therapeutic target for metabolic disease.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1643-1658"},"PeriodicalIF":10.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146225742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of a trans-ancestry polygenic risk score for type 1 diabetes.","authors":"Basile Jumentier, Hui-Qi Qu, Tianyuan Lu, Kai Liu, Erica L Kleinbrink, Kathleen Klein, Wiame Belbellaj, Isabel Gamache, Lauric Ferrat, Guillaume Butler-Laporte, Yangxi Li, Hakon Hakonarson, Wei Wu, Constantin Polychronakos, Celia M T Greenwood, Despoina Manousaki","doi":"10.1007/s00125-026-06706-5","DOIUrl":"10.1007/s00125-026-06706-5","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>The high heritability of type 1 diabetes has enabled the development of polygenic risk scores (PRSs) as disease risk screening tools. PRSs can identify individuals at the highest genetic risk in a population, who can benefit from autoantibody and metabolic surveillance, to avoid ketoacidosis at diagnosis and to access preventive therapies. However, PRSs for type 1 diabetes developed from European data perform less well in non-European ancestries. We aimed to develop a PRS with comparable performance among different ancestries.</p><p><strong>Methods: </strong>Using the PRS-CSx method, and data from large European, East Asian, African American and Hispanic type 1 diabetes genome-wide association studies (N_{total_cases}=29,469), we developed a trans-ancestry PRS (TA-PS), combining a non-HLA component incorporating over a million variants with the HLA component of a published European PRS (GRS2x). We tested the performance of the PRS using area under the receiver operating curve (AUROC), sensitivity and specificity in a multi-ancestry type 1 diabetes case-control cohort (N_total=4657; N_non-European=556) from Montreal, Canada. We validated our results in two independent type 1 diabetes case-control cohorts (Children's Hospital of Philadelphia, Center for Applied Genomics [CHOP-CAG] and Genetic Risk Assessment for Chinese Eaglet-T1D [GRACE]) and two population-based cohorts (All of Us and UK Biobank).</p><p><strong>Results: </strong>In the multi-ancestry Montreal-based cohort, TA-PS showed an AUROC of 0.89 which was significantly higher than the respective measure obtained with GRS2x in the same population (AUROC of 0.85). We obtained better overall sensitivity at the 90th percentile cut-off using TA-PS (0.71 in Europeans, 0.77 in South Asians), compared with sensitivity of 0.32 in African Americans and 0.56 in Europeans using GRS2x. The specificity obtained using TA-PS was slightly lower than that of GRS2x, albeit still acceptable (≥0.83 across all ancestries). These results were validated in the four independent cohorts.</p><p><strong>Conclusions/interpretation: </strong>We developed a trans-ancestry PRS that outperformed the European-based GRS2x. Importantly, TA-PS provides a comparable prediction in various ancestries, which supports its use in population-wide screening programmes.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1557-1568"},"PeriodicalIF":10.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147372300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal pre-pregnancy BMI differentially regulates intracellular pH in human umbilical vein endothelium from gestational diabetes mellitus pregnancies, with alkalinisation-associated reduction of adenosine transport in normal weight pregnancies.","authors":"Gonzalo Fuentes, Paola Valero, Marcelo Cornejo, Katherin Silva, Marco A Ramírez, Daniel R González, Jan-Luuk Hillebrands, Harry van Goor, Luis Sobrevia","doi":"10.1007/s00125-026-06679-5","DOIUrl":"10.1007/s00125-026-06679-5","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Gestational diabetes mellitus (GDM) is associated with fetoplacental endothelial dysfunction, including impaired extracellular clearance of adenosine, a vasodilator, in HUVECs. This study investigated the regulation of intracellular pH (pHi) and its impact on adenosine membrane transport in HUVECs. The hypothesis of this study was that Na⁺/H⁺ exchanger (NHE) isoform 1 (NHE1)-dependent pHi regulation differs between normal and GDM pregnancies depending on maternal pre-pregnancy BMI, leading to differential human equilibrative nucleoside transporters-mediated adenosine transport.</p><p><strong>Methods: </strong>HUVECs were isolated from 43 women with normal pregnancies and 23 with type A1 GDM and further stratified by maternal pre-pregnancy BMI into subgroups with normal weight, overweight and obesity. Data were also analysed as pooled groups (BMI ≥20 kg/m²). pHi and dpHi/dt were assessed in cells preloaded with the pH-sensitive fluorescent probe 2,7-bicarboxyethyl-5,6-carboxyfluorescein acetoxymethyl ester (12 µmol/l), in the absence or presence of 20 mmol/l NH₄Cl (acid pulse), the general NHEs inhibitor 5-N,N-hexamethylene amiloride (5 µmol/l) or the NHE1-selective inhibitor zoniporide (100 nmol/l). Intrinsic buffering capacity and H⁺ flux were calculated. NHE1 protein abundance was quantified by western blotting, and adenosine transport kinetics (0-500 µmol/l, 10 s) were determined.</p><p><strong>Results: </strong>GDM was linked to intracellular alkalinisation (~0.6 pHi units vs normal pregnancies), increased activity of NHE1 and NHE isoforms 2 and 3 and reduced buffering capacity, with these effects varying by pre-pregnancy maternal BMI. Increased pHi recovery (~3.8-fold) and NHE1 activity (~4.8-fold) were observed in cells from women with GDM and pre-pregnancy overweight, while those with obesity (i.e. gestational diabesity) showed unaltered NHE1-mediated pHi recovery. Buffering capacity was reduced across most GDM groups, except in the overweight group. The GDM-reduced adenosine transport maximal capacity via human equilibrative nucleoside transporter isoform 2 was restored by intracellular acidification in GDM.</p><p><strong>Conclusions/interpretation: </strong>Pre-pregnancy maternal metabolic status influences endothelial adaptation or maladaptation to GDM. Stratifying GDM cases by pre-pregnancy maternal BMI uncovers subgroup-specific physiological responses, highlighting the importance of tailored approaches in understanding GDM pathophysiology.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1618-1642"},"PeriodicalIF":10.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147282786","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":"Association of corneal nerve parameters with nerve abnormalities and neuropathic pain in prediabetes and type 2 diabetes: the Maastricht Study.","authors":"Mette K Borbjerg, Sara Mokhtar, Nadia Sutedja, Annemarie Koster, Carsten D Mørch, Tos T J M Berendschot, Nicolaas Schaper, Niels Ejskjaer, Johan Røikjer","doi":"10.1007/s00125-026-06676-8","DOIUrl":"10.1007/s00125-026-06676-8","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Corneal confocal microscopy is a valuable technique for assessing neuropathy; however, whether it can distinguish painful from painless neuropathy remains uncertain and existing evidence is based on the results of smaller studies. This study assessed the association of corneal nerve parameters with abnormalities identified by electromyography (EMG) and neuropathic pain in a large population with and without (pre)diabetes.</p><p><strong>Methods: </strong>In this study we included cross-sectional data for 3425 participants from the Maastricht Study. Wide-field corneal confocal microscopy (WF-CCM) was performed using fully automated analysis of three corneal nerve parameters: corneal nerve branch density (CNBD), corneal nerve fibre density (CNFD) and corneal nerve fibre length (CNFL). An axonal degeneration composite score comprising compound muscle action potential amplitudes (peroneal and tibial) and the sensory nerve action potential amplitude of the sural nerve was created by categorising EMG amplitudes as normal or indicating minor (≤10th percentile), moderate (≤5th percentile) or severe (≤2.5th percentile) abnormalities. Neuropathic pain was determined as a modified Douleur Neuropathique en 4 Questions (DN4) interview score ≥3.</p><p><strong>Results: </strong>The mean age of the participants was 59.2 years; 51.6% were female, 15% had prediabetes (defined as impaired fasting glucose, impaired glucose tolerance or both) and 19% had type 2 diabetes. The median diabetes duration was 3.0 years. Regression analyses revealed statistically significant associations between the axonal degeneration EMG score and WF-CCM parameters (CNFL: β=-0.51 [95% CI -0.78, -0.24]; CNFD: β=-1.56 [95% CI -3.04, -0.08]; CNBD: β=-3.08 [95% CI -5.51, -0.64]; all p<0.05) but no statistically significant associations between neuropathic pain and WF-CCM parameters (CNFL: β=-0.06; CNFD: β=-1.15; CNBD: β=-0.22; all p>0.1).</p><p><strong>Conclusions/interpretation: </strong>The study found associations between the axonal degeneration EMG score and WF-CCM, but no associations were observed between neuropathic pain and WF-CCM parameters, suggesting that WF-CCM has limited value in assessing neuropathic pain.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1519-1531"},"PeriodicalIF":10.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise in type 1 diabetes: real-world data on glucose levels and hypoglycaemia risk from over 420,000 exercise sessions.","authors":"Josip Zivkovic, Michael Mitter, Delphine Theodorou, Othmar Moser, Timor Glatzer","doi":"10.1007/s00125-026-06672-y","DOIUrl":"10.1007/s00125-026-06672-y","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>This large observational cohort real-world study explored the effects of three forms of exercise (walking [WALK], aerobic excluding walking [AER] and anaerobic [ANAER]) on glucose levels and hypoglycaemia risk in type 1 diabetes.</p><p><strong>Methods: </strong>Data were collected from 3248 users of mySugr Logbook and Apple Health (mean ± SD age 41.23±12.25 years; glucose management index of 7.05±1.09%; 41.5% were female) over a total of 428,058 exercise sessions. Acute and 24 h glycaemic effects were examined across exercise types. Post-exercise glycaemia data over 24 h were compared with sedentary glycaemic data. Time of exercise was used to assess the probability of nocturnal hypoglycaemia.</p><p><strong>Results: </strong>Independent of type, exercise decreased glucose by -1.06±0.89 mmol/l. For the individual types of exercise, WALK decreased levels by -1.24±0.81 mmol/l, AER by -1.43±1.02 mmol/l and ANAER by -0.52±0.81 mmol/l (all p<0.001). Comparing sedentary days vs active days, the time in range (3.9-10 mmol/l glucose) increased by +2.08±6.06% for WALK, +2.94±6.46% for AER and +3.93±7.16% for ANAER, and the time below range (<3.9 mmol/l) increased by 0.37±1.57% for WALK, 0.74±1.70% for AER and 0.68±1.79% for ANAER (all p<0.001). ANAER yielded a smaller chance of acute hypoglycaemia and WALK yielded a smaller chance of nocturnal hypoglycaemia (p<0.001). Activities done after 15:30 hours did not increase the risk of nocturnal hypoglycaemia when compared with earlier exercise sessions (+0.9±0.34%; p<0.01).</p><p><strong>Conclusions/interpretation: </strong>Aerobic activities decreased glucose more during exercise sessions than anaerobic exercise and yielded larger acute hypoglycaemia risk; anaerobic activities yielded the largest 24 h glycaemic improvements. More-intense exercise resulted in a larger nocturnal hypoglycaemia than walking; exercise timing was not a relevant contributor to nocturnal hypoglycaemia.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1457-1467"},"PeriodicalIF":10.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146178203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-designing a new clinical pathway to support families with children identified as having early-stage type 1 diabetes in Western Australia.","authors":"Sarah K P Black, Alexandra Tully, Elizabeth A Davis, Alison Roberts, Sabrina Binkowski, Leanne Cromb, Craig Taplin, Brydie-Rose Mellor, Keely Bebbington, Aveni Haynes","doi":"10.1007/s00125-026-06668-8","DOIUrl":"10.1007/s00125-026-06668-8","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Children with early-stage (pre-symptomatic) type 1 diabetes are currently identified primarily via research-based screening programmes in Australia. Once identified, families live with the knowledge that their child has an increased chance of developing symptomatic, lifelong, insulin-requiring type 1 diabetes but have no specific clinical pathway available to them in Western Australia (WA) for accessing tailored support or education. This project aimed to co-design a new clinical pathway to address this unmet need.</p><p><strong>Methods: </strong>Experience-based co-design (EBCD) methodology was applied, comprising three phases undertaken consecutively over 12 months. Recruitment for each phase was via open invitation with voluntary participation. Phases 1 and 2 involved facilitated community conversations and focus groups conducted separately for type 1 diabetes community members and healthcare professionals (HCPs). Data from these phases were analysed using deductive and inductive content analysis to identify key categories of information and a prototype clinical pathway was developed incorporating these. For phase 3, a combined workshop was held with all stakeholders to obtain feedback on the prototype, and refine it accordingly.</p><p><strong>Results: </strong>In phase 1, 16 community members (people living with type 1 diabetes, families whose child or children had been screened for type 1 diabetes) and 36 HCPs (doctors, nurse educators, social workers, dietitians, a mental health nurse and administrative staff from Perth Children's Hospital) participated in separate community conversations. The following three key categories were identified: (1) the need for education; (2) the need for support and strategies for managing uncertainty; and (3) the need for information on disease-modifying therapies and access to clinical trials. In phase 2, seven community members and 11 HCPs participated in separate focus groups. The following key priorities were identified: (1) the need for access to HCPs skilled in supporting patients to manage uncertainty; (2) the need for flexibility in delivery modes (telehealth/in-person); (3) the need for early referral to relevant clinical trials; and (4) the need for reliable and up-to-date resources. In phase 3, three community members and three HCPs attended a combined workshop to provide feedback on a prototype clinical pathway and their feedback was incorporated into a final version.</p><p><strong>Conclusions/interpretation: </strong>Application of EBCD methodology enabled the development of a new clinical pathway tailored to the needs of WA families with a child living with early-stage type 1 diabetes.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1444-1456"},"PeriodicalIF":10.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The diabetes-associated K⁺ channel TALK-2 controls human beta cell endoplasmic reticulum Ca²⁺ handling, which promotes basal insulin release and limits glucose-stimulated insulin secretion.","authors":"Jordyn R Dobson, Prasanna K Dadi, Matthew T Dickerson, Arya Y Nakhe, Soma Behera, Shannon E Gibson, Spencer J Peachee, Anthony Piron, Miriam Cnop, David A Jacobson","doi":"10.1007/s00125-026-06683-9","DOIUrl":"10.1007/s00125-026-06683-9","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Aims/hypothesis: &lt;/strong&gt;The two-pore domain K&lt;sup&gt;+&lt;/sup&gt; channel TWIK1-related alkalinisation-activated K&lt;sup&gt;+&lt;/sup&gt; channel 2 (TALK-2) is encoded by KCNK17, which is one of the most abundant beta cell K&lt;sup&gt;+&lt;/sup&gt; channel transcripts that also shows high islet expression specificity. Polymorphisms that increase islet KNCK17 expression or result in TALK-2 gain-of-function are associated with a predisposition for developing type 2 diabetes. However, there is a gap in knowledge of the beta cell function(s) of TALK-2. As K&lt;sup&gt;+&lt;/sup&gt; channels typically control beta cell Ca&lt;sup&gt;2+&lt;/sup&gt; handling, we aimed to examine the TALK-2 channel control of beta cell Ca&lt;sup&gt;2+&lt;/sup&gt; homeostasis and the resulting impact on insulin secretion.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Localisation of TALK-2 was evaluated with immunofluorescent staining as well as TALK-2-GFP construct co-expressed with intracellular markers. TALK-2 function was evaluated by measuring changes in cytoplasmic Ca&lt;sup&gt;2+&lt;/sup&gt; (Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;C&lt;/sub&gt;), endoplasmic reticulum Ca&lt;sup&gt;2+&lt;/sup&gt; (Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;ER&lt;/sub&gt;), ER membrane potential (V&lt;sub&gt;m&lt;/sub&gt;), K&lt;sup&gt;+&lt;/sup&gt; currents and insulin secretion in a TALK-2 inducible cell line and/or primary human beta cells with adenoviral-mediated shRNA knockdown (KD) of TALK-2 or scramble shRNA.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;TALK-2 protein localised to the plasma membrane and ER membrane, and formed functional channels on the ER membrane. Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;ER&lt;/sub&gt; release was accelerated by TALK-2 (slope for TALK-2-expressing cells vs controls: 14.8 ± 0.7 vs 8.9 ± 1.3, respectively, shown as mean ± SE), which reduced Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;ER&lt;/sub&gt; storage (ΔCa&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;ER&lt;/sub&gt; amplitude: TALK-2-expressing cells reduced by 25 ± 5%) and increased basal relative Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;C&lt;/sub&gt; (fold increase by 12 ± 2%). Furthermore, TALK-2 diminished ER membrane hyperpolarisation following Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;ER&lt;/sub&gt; release (Accelerated Sensor of Action Potentials [ASAP3&lt;sub&gt;ER&lt;/sub&gt;] amplitude decreased by 20 ± 0.8% in TALK-2-expressing cells), suggesting that TALK-2 strengthens the electrical driving force for Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;ER&lt;/sub&gt; leak. In human beta cells, TALK-2-KD increased Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;ER&lt;/sub&gt; stores by reducing Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;ER&lt;/sub&gt; leak (2.30 ± 0.12 vs controls 2.65 ± 0.14). Moreover, TALK-2-KD reduced beta cell Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;C&lt;/sub&gt; at euglycaemic conditions (2.88 ± 0.36 vs controls 3.16 ± 0.36) and increased beta cell Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;C&lt;/sub&gt; influx in response to hyperglycaemic conditions (4.07 ± 0.55 vs controls 3.45 ± 0.48). Human pseudoislets with beta cell-specific TALK-2-KD displayed reduced basal insulin secretion (0.266 ± 0.065 vs controls 0.432 ± 0.073) and enhanced glucose-stimulated insulin secretion (GSIS; 85.01 ± 13.96 vs controls 42.53 ± 5.52).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions/interpretation: &lt;/strong&gt;These data support the notion that TALK-2 functions on the human beta cell ","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"1581-1599"},"PeriodicalIF":10.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147282781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}