Pub Date : 2026-01-18DOI: 10.1007/s00125-025-06652-8
Orhan K Öz,Amber M Sherwood,Peter A Crisologo,Amanda L Killeen,Kavita Bhavan,Javier La Fontaine,Katie L Rubitschung,Helena Hwang,Robert W Haley,Lawrence A Lavery
AIMS/HYPOTHESISOsteomyelitis is a common complication of diabetic foot ulcers and a leading cause of lower limb amputations globally. Accurate diagnosis of diabetic foot osteomyelitis (DFO) is essential for effective infection management and improving prognosis. This study aimed to compare the performance of white blood cell (WBC)-single photon emission computed tomography (SPECT)/computed tomography (CT) and conventional MRI in the initial diagnosis of DFO and in detecting residual infection during treatment monitoring, using bone biopsy as the reference standard.METHODSIn this prospective clinical study, 47 patients with foot wounds suspicious for DFO underwent 99mTc-WBC SPECT/CT and MRI, followed by bone biopsy. After receiving a standard course of antibiotics, 20 patients returned for post-treatment imaging and a repeat biopsy. All imaging studies and histopathology were blindly interpreted as positive or negative for DFO. Biopsies were considered positive if either bone cultures or histopathology indicated osteomyelitis. Imaging results were evaluated against biopsy to determine the diagnostic performance of each method before and after treatment.RESULTSFor initial DFO diagnosis, WBC SPECT/CT demonstrated sensitivity, specificity, positive predictive value and negative predictive value of 85%, 79%, 90% and 69%, respectively, while MRI yielded corresponding values of 73%, 43%, 75% and 40%. Following antibiotic therapy, WBC SPECT/CT and MRI shared identical sensitivities, specificities, positive predictive values and negative predictive values of 75%, 75%, 43% and 92%.CONCLUSIONS/INTERPRETATIONWBC SPECT/CT exhibits greater sensitivity and specificity than MRI at initial diagnosis. However, after treatment, WBC SPECT/CT and MRI perform equivalently in determining therapeutic response. Our results indicate WBC SPECT/CT is a viable, if not superior, method for primary non-invasive assessment of suspected DFO. To our knowledge, this is the first study to use paired bone biopsy to validate imaging in diabetic foot infections both before and after antibiotic intervention.
{"title":"Prospective comparison of WBC SPECT/CT and conventional MRI for diagnosing osteomyelitis and monitoring treatment response in diabetic foot infections.","authors":"Orhan K Öz,Amber M Sherwood,Peter A Crisologo,Amanda L Killeen,Kavita Bhavan,Javier La Fontaine,Katie L Rubitschung,Helena Hwang,Robert W Haley,Lawrence A Lavery","doi":"10.1007/s00125-025-06652-8","DOIUrl":"https://doi.org/10.1007/s00125-025-06652-8","url":null,"abstract":"AIMS/HYPOTHESISOsteomyelitis is a common complication of diabetic foot ulcers and a leading cause of lower limb amputations globally. Accurate diagnosis of diabetic foot osteomyelitis (DFO) is essential for effective infection management and improving prognosis. This study aimed to compare the performance of white blood cell (WBC)-single photon emission computed tomography (SPECT)/computed tomography (CT) and conventional MRI in the initial diagnosis of DFO and in detecting residual infection during treatment monitoring, using bone biopsy as the reference standard.METHODSIn this prospective clinical study, 47 patients with foot wounds suspicious for DFO underwent 99mTc-WBC SPECT/CT and MRI, followed by bone biopsy. After receiving a standard course of antibiotics, 20 patients returned for post-treatment imaging and a repeat biopsy. All imaging studies and histopathology were blindly interpreted as positive or negative for DFO. Biopsies were considered positive if either bone cultures or histopathology indicated osteomyelitis. Imaging results were evaluated against biopsy to determine the diagnostic performance of each method before and after treatment.RESULTSFor initial DFO diagnosis, WBC SPECT/CT demonstrated sensitivity, specificity, positive predictive value and negative predictive value of 85%, 79%, 90% and 69%, respectively, while MRI yielded corresponding values of 73%, 43%, 75% and 40%. Following antibiotic therapy, WBC SPECT/CT and MRI shared identical sensitivities, specificities, positive predictive values and negative predictive values of 75%, 75%, 43% and 92%.CONCLUSIONS/INTERPRETATIONWBC SPECT/CT exhibits greater sensitivity and specificity than MRI at initial diagnosis. However, after treatment, WBC SPECT/CT and MRI perform equivalently in determining therapeutic response. Our results indicate WBC SPECT/CT is a viable, if not superior, method for primary non-invasive assessment of suspected DFO. To our knowledge, this is the first study to use paired bone biopsy to validate imaging in diabetic foot infections both before and after antibiotic intervention.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"9 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994878","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}
Pub Date : 2026-01-15DOI: 10.1007/s00125-025-06647-5
Nicolette J D Verhoog,Donita Africander,Karl-Heinz Storbeck
Androgens and oestrogens differentially regulate metabolic processes that impact the development of type 2 diabetes in women. The biological actions of these sex steroids are, however, dependent on their bioavailability, which is regulated by their carrier protein sex hormone-binding globulin (SHBG). However, SHBG itself plays a role in the risk of developing type 2 diabetes, independent of the sex steroid. The molecular mechanisms underlying the effects of androgens, oestrogens and SHBG in the pathogenesis of type 2 diabetes in women are complex and multifaceted, spanning various insulin-sensitive tissues. This review explores the current knowledge on these topics and provides a mechanistic framework that integrates current experimental and clinical findings, providing insights into sex steroid-specific pathways and the sex steroid-independent effects of SHBG. Finally, the review highlights the need for further studies using appropriate models to delineate the relationship between androgens, 17β-oestradiol, SHBG and type 2 diabetes, with a view to translating these findings to improve women's health.
{"title":"Sex steroids, SHBG and type 2 diabetes in women: what do we really know?","authors":"Nicolette J D Verhoog,Donita Africander,Karl-Heinz Storbeck","doi":"10.1007/s00125-025-06647-5","DOIUrl":"https://doi.org/10.1007/s00125-025-06647-5","url":null,"abstract":"Androgens and oestrogens differentially regulate metabolic processes that impact the development of type 2 diabetes in women. The biological actions of these sex steroids are, however, dependent on their bioavailability, which is regulated by their carrier protein sex hormone-binding globulin (SHBG). However, SHBG itself plays a role in the risk of developing type 2 diabetes, independent of the sex steroid. The molecular mechanisms underlying the effects of androgens, oestrogens and SHBG in the pathogenesis of type 2 diabetes in women are complex and multifaceted, spanning various insulin-sensitive tissues. This review explores the current knowledge on these topics and provides a mechanistic framework that integrates current experimental and clinical findings, providing insights into sex steroid-specific pathways and the sex steroid-independent effects of SHBG. Finally, the review highlights the need for further studies using appropriate models to delineate the relationship between androgens, 17β-oestradiol, SHBG and type 2 diabetes, with a view to translating these findings to improve women's health.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"56 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968392","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}
Pub Date : 2026-01-15DOI: 10.1007/s00125-025-06646-6
Kagan E Karakus,Lexie Chesshir,Sonya Walker,Erin E Baschal,Kristen A McDaniel,Taylor M Triolo,Andrea K Steck,Brigitte I Frohnert,Peter A Gottlieb,Aaron W Michels,Kimber M Simmons
AIMS/HYPOTHESISThis is the first real-world prospective observational study of teplizumab use following approval by the United States Food and Drug Administration in individuals with stage 2 type 1 diabetes. We examined whether glycaemic responses observed in controlled trials were reproduced in real-world practice and explored immunological biomarkers associated with treatment.METHODSChildren and adults with stage 2 type 1 diabetes were prospectively followed in the Early Type 1 Diabetes Clinic at the Barbara Davis Center. Individuals who received teplizumab between April 2023 and February 2025 (n=30) were compared with an untreated group (n=10). Key assessments included OGTTs, HbA1c measurements and continuous glucose monitoring (CGM) data, collected before and after treatment. Longitudinal metabolic data were available for up to 22 treated participants, with follow-up assessments occurring between 2 and 13 months after treatment. Changes in Epstein-Barr virus (EBV) and islet antigen-targeting T cell receptor (TCR) β chains were measured longitudinally from genomic DNA via a PCR-based targeted TCR sequencing assay.RESULTSAmong treated individuals followed up between 2 and 6 months after treatment, OGTT 2 h glucose improved (10.7 ± 2.1 to 8.8 ± 2.8 mmol/l, p=0.007), as did HbA1c (40 ± 4 to 39 ± 6 mmol/mol [5.8 ± 0.4% to 5.7 ± 0.5%], p=0.044). In addition, 67% had a stable or reduced CGM time ≥7.8 mmol/l. CD4 preproinsulin-specific TCRs declined after treatment, with no change in the untreated group. These reductions correlated with higher C-peptide AUC (r=-0.656, p=0.013). EBV TCR sequences were similar before and after teplizumab treatment.CONCLUSIONS/INTERPRETATIONTeplizumab can be safely and effectively administered in clinical practice. Early glycaemic improvements and reductions in CD4 preproinsulin-specific TCRs suggest that post-treatment immunological changes may serve as biomarkers to guide early-stage intervention.
{"title":"Teplizumab treatment for stage 2 type 1 diabetes: a real-world evaluation of metabolic and immunological outcomes.","authors":"Kagan E Karakus,Lexie Chesshir,Sonya Walker,Erin E Baschal,Kristen A McDaniel,Taylor M Triolo,Andrea K Steck,Brigitte I Frohnert,Peter A Gottlieb,Aaron W Michels,Kimber M Simmons","doi":"10.1007/s00125-025-06646-6","DOIUrl":"https://doi.org/10.1007/s00125-025-06646-6","url":null,"abstract":"AIMS/HYPOTHESISThis is the first real-world prospective observational study of teplizumab use following approval by the United States Food and Drug Administration in individuals with stage 2 type 1 diabetes. We examined whether glycaemic responses observed in controlled trials were reproduced in real-world practice and explored immunological biomarkers associated with treatment.METHODSChildren and adults with stage 2 type 1 diabetes were prospectively followed in the Early Type 1 Diabetes Clinic at the Barbara Davis Center. Individuals who received teplizumab between April 2023 and February 2025 (n=30) were compared with an untreated group (n=10). Key assessments included OGTTs, HbA1c measurements and continuous glucose monitoring (CGM) data, collected before and after treatment. Longitudinal metabolic data were available for up to 22 treated participants, with follow-up assessments occurring between 2 and 13 months after treatment. Changes in Epstein-Barr virus (EBV) and islet antigen-targeting T cell receptor (TCR) β chains were measured longitudinally from genomic DNA via a PCR-based targeted TCR sequencing assay.RESULTSAmong treated individuals followed up between 2 and 6 months after treatment, OGTT 2 h glucose improved (10.7 ± 2.1 to 8.8 ± 2.8 mmol/l, p=0.007), as did HbA1c (40 ± 4 to 39 ± 6 mmol/mol [5.8 ± 0.4% to 5.7 ± 0.5%], p=0.044). In addition, 67% had a stable or reduced CGM time ≥7.8 mmol/l. CD4 preproinsulin-specific TCRs declined after treatment, with no change in the untreated group. These reductions correlated with higher C-peptide AUC (r=-0.656, p=0.013). EBV TCR sequences were similar before and after teplizumab treatment.CONCLUSIONS/INTERPRETATIONTeplizumab can be safely and effectively administered in clinical practice. Early glycaemic improvements and reductions in CD4 preproinsulin-specific TCRs suggest that post-treatment immunological changes may serve as biomarkers to guide early-stage intervention.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"17 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968393","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}
Pub Date : 2026-01-15DOI: 10.1007/s00125-025-06655-5
Faye D Baldwin,Khaled F Bedair,Andrea L Jorgensen,Lewis Green,Innocent G Asiimwe,Colin N A Palmer,Archie Campbell,Caroline Hayward,Qing Pan,Shiyu Shu,Josephine H Li, ,Ewan R Pearson,Munir Pirmohamed,Daniel F Carr
AIMS/HYPOTHESISMetformin, a mainstay of treatment for type 2 diabetes, can cause vitamin B12 deficiency. Clinical risk factors have been identified but genetic factors remain undiscovered. Our objective was to identify and validate genetic predisposing factors and establish clinical utility.METHODSIndividuals with metformin-induced vitamin B12 deficiency (n=487) and metformin-tolerant control individuals (n=6686) were identified in UK Biobank. Genome-wide association analysis was undertaken using logistic regression. Replication was undertaken in three cohorts: a Scottish cohort; the Diabetes Prevention Program Outcomes Study (DPPOS); and a separate cohort from Liverpool. In the Liverpool cohort, plasma metformin levels were also measured.RESULTSAnalysis identified a genome-wide significant non-synonymous SNP in the cubilin gene (CUBN, rs1801222/p.S253F) associated with metformin-induced vitamin B12 deficiency (additive model; adjusted p=1.86×10-10; OR 1.56 [95% CI 1.36, 1.79] for AG vs GG genotype; OR 2.43 [95% CI 1.85, 3.20] for AA vs GG genotype), which was replicated in both the Scottish and the DPPOS cohorts. Vitamin B12 deficiency occurred in 0.84-1.20% of non-metformin-exposed individuals regardless of rs1801222 genotype. However, a large interaction with metformin use was observed, with vitamin B12 deficiency occurring at 6.02% in GG, 7.96% in GA and 12.84% in AA genotype groups. When followed up from metformin initiation, 10% with the AA genotype were vitamin B12 deficient by 11 years vs 21 years for 10% of the GG group.CONCLUSIONS/INTERPRETATIONThe observed genetic association suggests that the rs180122 genotype should be considered a significant risk factor for metformin-induced vitamin B12 deficiency. While clinical monitoring of serum vitamin B12 levels in patients on metformin is inconsistently done, this finding highlights the potential clinical utility of targeted monitoring for certain subsets of individuals, including those genetically at high risk.
目的/假设二甲双胍是治疗2型糖尿病的主要药物，可导致维生素B12缺乏。临床危险因素已经确定，但遗传因素仍未发现。我们的目的是确定和验证遗传易感因素，并建立临床应用。方法在英国生物银行（UK Biobank）鉴定二甲双胍诱导的维生素B12缺乏症（n=487）和二甲双胍耐受对照（n=6686）。采用logistic回归进行全基因组关联分析。在三个队列中进行了重复研究：苏格兰队列；糖尿病预防项目结果研究（DPPOS）；另一组来自利物浦。在利物浦队列中，也测量了血浆二甲双胍水平。结果在cubilin基因（CUBN, rs1801222/p）中发现了一个全基因组显著的非同义SNP。S253F)与二甲双胍诱导的维生素B12缺乏症相关（加性模型；校正p=1.86×10-10； AG与GG基因型的OR为1.56 [95% CI 1.36, 1.79]； AA与GG基因型的OR为2.43 [95% CI 1.85, 3.20]），该结果在苏格兰和DPPOS队列中都得到了重复。无论rs1801222基因型如何，非二甲双胍暴露个体中维生素B12缺乏症发生率为0.84-1.20%。然而，与二甲双胍的使用有很大的相互作用，GG、GA和AA基因型组维生素B12缺乏率分别为6.02%、7.96%和12.84%。当从二甲双胍开始随访时，10%的AA基因型缺乏维生素B12 11年，而10%的GG组缺乏维生素B12 21年。结论/解释观察到的遗传关联提示rs180122基因型应被认为是二甲双胍诱导的维生素B12缺乏症的重要危险因素。虽然对服用二甲双胍的患者血清维生素B12水平的临床监测并不一致，但这一发现强调了对某些个体亚群（包括那些遗传上高风险的个体）进行针对性监测的潜在临床效用。
{"title":"Identification of a genetic risk factor for metformin-induced vitamin B12 deficiency.","authors":"Faye D Baldwin,Khaled F Bedair,Andrea L Jorgensen,Lewis Green,Innocent G Asiimwe,Colin N A Palmer,Archie Campbell,Caroline Hayward,Qing Pan,Shiyu Shu,Josephine H Li, ,Ewan R Pearson,Munir Pirmohamed,Daniel F Carr","doi":"10.1007/s00125-025-06655-5","DOIUrl":"https://doi.org/10.1007/s00125-025-06655-5","url":null,"abstract":"AIMS/HYPOTHESISMetformin, a mainstay of treatment for type 2 diabetes, can cause vitamin B12 deficiency. Clinical risk factors have been identified but genetic factors remain undiscovered. Our objective was to identify and validate genetic predisposing factors and establish clinical utility.METHODSIndividuals with metformin-induced vitamin B12 deficiency (n=487) and metformin-tolerant control individuals (n=6686) were identified in UK Biobank. Genome-wide association analysis was undertaken using logistic regression. Replication was undertaken in three cohorts: a Scottish cohort; the Diabetes Prevention Program Outcomes Study (DPPOS); and a separate cohort from Liverpool. In the Liverpool cohort, plasma metformin levels were also measured.RESULTSAnalysis identified a genome-wide significant non-synonymous SNP in the cubilin gene (CUBN, rs1801222/p.S253F) associated with metformin-induced vitamin B12 deficiency (additive model; adjusted p=1.86×10-10; OR 1.56 [95% CI 1.36, 1.79] for AG vs GG genotype; OR 2.43 [95% CI 1.85, 3.20] for AA vs GG genotype), which was replicated in both the Scottish and the DPPOS cohorts. Vitamin B12 deficiency occurred in 0.84-1.20% of non-metformin-exposed individuals regardless of rs1801222 genotype. However, a large interaction with metformin use was observed, with vitamin B12 deficiency occurring at 6.02% in GG, 7.96% in GA and 12.84% in AA genotype groups. When followed up from metformin initiation, 10% with the AA genotype were vitamin B12 deficient by 11 years vs 21 years for 10% of the GG group.CONCLUSIONS/INTERPRETATIONThe observed genetic association suggests that the rs180122 genotype should be considered a significant risk factor for metformin-induced vitamin B12 deficiency. While clinical monitoring of serum vitamin B12 levels in patients on metformin is inconsistently done, this finding highlights the potential clinical utility of targeted monitoring for certain subsets of individuals, including those genetically at high risk.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"266 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971828","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}
Pub Date : 2026-01-15DOI: 10.1007/s00125-025-06649-3
Stephanie Bourgeois,Annelore Van Mulders,Yves Heremans,Gunter Leuckx,Lien Willems,Sophie Coenen,Laure Degroote,Julie Pierreux,Daliya Kancheva,Isabelle Scheyltjens,Kiavash Movahedi,Françoise Carlotti,Eelco de Koning,Xiaoyan Yi,Chiara Vinci,Yue Tong,Miriam Cnop,Harry Heimberg,Nico De Leu,Willem Staels
AIMS/HYPOTHESISRegenerating endogenous pancreatic beta cells is a potentially curative yet currently elusive strategy for diabetes therapy. Mimicking the microenvironment of the developing pancreas and leveraging vascular signals that support pancreatic endocrinogenesis may promote beta cell regeneration. We aimed to investigate whether recovery from experimental hypovascularisation of the endocrine pancreas could trigger mouse beta cell proliferation.METHODSA doxycycline (DOX)-inducible transgenic mouse model was used to induce conditional intra-islet hypovascularisation. In this model, vascular endothelial growth factor (VEGF)-A signalling within pancreatic islets is antagonised through beta cell-specific overexpression of a VEGF-A decoy receptor, soluble fms-like tyrosine kinase 1 (sFLT1). Cessation of sFLT1 overexpression was induced by DOX withdrawal. sFLT1 expression, vessel kinetics and beta cell proliferation upon DOX administration and withdrawal were analysed using quantitative RT-PCR and immunostaining. Single-cell RNA-seq was used to investigate the effects on the islet cells' transcriptome and perform pathway enrichment analysis. RIP-rtTA;TetO-GFP mice were studied in parallel to assess the dependency of cell cycle induction on vessel manipulation. Additionally, in vitro experiments were conducted to further elucidate and validate our in vivo findings.RESULTSSerendipitously, we discovered that sFLT1 overexpression in beta cells induces endoplasmic reticulum (ER) stress and activates proliferation-associated pathways. Upon cessation of sFLT1 overexpression, ER stress decreased and beta cell proliferation was promoted independently of vessel recovery, as shown by cumulative BrdU labelling over 7 days (mean ± SEM vs control: 14.3 ± 1.3% vs 5.2 ± 0.6%) during the DOX withdrawal period. Transient GFP overexpression also induced ER stress and a subsequent reduction thereof resulted in increased beta cell proliferation (mean ± SEM vs control: 7.2 ± 0.4% vs 5.1 ± 0.5%). Chemical, transient induction of ER stress in vitro by ER-stress-inducing compounds reproduced this beta cell cycling response, as assessed by cumulative EdU labelling during a 3 day washout period (mean ± SEM vs control: 2.6 ± 0.4% vs 0.8 ± 0.2% for thapsigargin and 3.8 ± 0.9% vs 1.0 ± 0.2% for tunicamycin), which further increased under high-glucose conditions when islets were exposed to thapsigargin (mean ± SEM vs control: 9.0 ± 1.2% vs 2.0 ± 0.4%).CONCLUSIONS/INTERPRETATIONOur findings uncover a link between transgene (over)expression, ER stress, glucose and cell cycle activation in mouse beta cells.DATA AND CODE AVAILABILITYThe single-cell RNA-seq data generated in this study are deposited at GEO (NCBI) with accession code GSE274443.
目的/假设再生内源性胰腺β细胞是一种潜在的治疗糖尿病的策略，但目前尚不明确。模拟发育中的胰腺微环境和利用支持胰腺内分泌发生的血管信号可能促进β细胞再生。我们的目的是研究从实验性胰腺内分泌血管减少中恢复是否会触发小鼠β细胞增殖。方法采用多西环素（DOX）诱导的转基因小鼠模型诱导条件胰岛内低血管化。在该模型中，胰岛内的血管内皮生长因子(VEGF)-A信号通过β细胞特异性过表达VEGF-A诱骗受体，可溶性fms样酪氨酸激酶1 （sFLT1）被拮抗。停用DOX可诱导sFLT1过表达的停止。使用定量RT-PCR和免疫染色分析sFLT1表达、血管动力学和β细胞增殖在DOX给药和停药后的变化。单细胞RNA-seq用于研究对胰岛细胞转录组的影响，并进行途径富集分析。RIP-rtTA;平行研究TetO-GFP小鼠，以评估血管操作对细胞周期诱导的依赖性。此外，我们还进行了体外实验来进一步阐明和验证我们在体内的发现。结果我们偶然发现sFLT1在β细胞中的过表达可诱导内质网（ER）应激并激活增殖相关途径。停止sFLT1过表达后，内质膜应激降低，β细胞增殖独立于血管恢复而得到促进，正如在DOX停药期间7天内累积BrdU标记所显示的那样（平均±SEM vs对照组：14.3±1.3% vs 5.2±0.6%）。瞬时GFP过表达也会诱导内质网应激，随后的内质网应激降低导致β细胞增殖增加（平均±SEM vs对照组：7.2±0.4% vs 5.1±0.5%）。通过3天洗脱期的累积EdU标记（平均±SEM vs对照组：2.6±0.4% vs 0.8±0.2% thapsigargin, 3.8±0.9% vs 1.0±0.2% tunicamycin）来评估，内质酰胺应激诱导化合物在体外的化学瞬时诱导内质酰胺应激重现了这种β细胞循环反应，当胰岛暴露于thapsigargin时，高糖条件下进一步增加（平均±SEM vs对照组：9.0±1.2% vs 2.0±0.4%）。结论/解释：我们的研究结果揭示了小鼠β细胞中转基因（过）表达、内质网应激、葡萄糖和细胞周期激活之间的联系。数据和代码可用性本研究生成的单细胞RNA-seq数据存放在GEO (NCBI)，登录代码为GSE274443。
{"title":"Transient ER stress cell-autonomously promotes beta cell cycling in mice.","authors":"Stephanie Bourgeois,Annelore Van Mulders,Yves Heremans,Gunter Leuckx,Lien Willems,Sophie Coenen,Laure Degroote,Julie Pierreux,Daliya Kancheva,Isabelle Scheyltjens,Kiavash Movahedi,Françoise Carlotti,Eelco de Koning,Xiaoyan Yi,Chiara Vinci,Yue Tong,Miriam Cnop,Harry Heimberg,Nico De Leu,Willem Staels","doi":"10.1007/s00125-025-06649-3","DOIUrl":"https://doi.org/10.1007/s00125-025-06649-3","url":null,"abstract":"AIMS/HYPOTHESISRegenerating endogenous pancreatic beta cells is a potentially curative yet currently elusive strategy for diabetes therapy. Mimicking the microenvironment of the developing pancreas and leveraging vascular signals that support pancreatic endocrinogenesis may promote beta cell regeneration. We aimed to investigate whether recovery from experimental hypovascularisation of the endocrine pancreas could trigger mouse beta cell proliferation.METHODSA doxycycline (DOX)-inducible transgenic mouse model was used to induce conditional intra-islet hypovascularisation. In this model, vascular endothelial growth factor (VEGF)-A signalling within pancreatic islets is antagonised through beta cell-specific overexpression of a VEGF-A decoy receptor, soluble fms-like tyrosine kinase 1 (sFLT1). Cessation of sFLT1 overexpression was induced by DOX withdrawal. sFLT1 expression, vessel kinetics and beta cell proliferation upon DOX administration and withdrawal were analysed using quantitative RT-PCR and immunostaining. Single-cell RNA-seq was used to investigate the effects on the islet cells' transcriptome and perform pathway enrichment analysis. RIP-rtTA;TetO-GFP mice were studied in parallel to assess the dependency of cell cycle induction on vessel manipulation. Additionally, in vitro experiments were conducted to further elucidate and validate our in vivo findings.RESULTSSerendipitously, we discovered that sFLT1 overexpression in beta cells induces endoplasmic reticulum (ER) stress and activates proliferation-associated pathways. Upon cessation of sFLT1 overexpression, ER stress decreased and beta cell proliferation was promoted independently of vessel recovery, as shown by cumulative BrdU labelling over 7 days (mean ± SEM vs control: 14.3 ± 1.3% vs 5.2 ± 0.6%) during the DOX withdrawal period. Transient GFP overexpression also induced ER stress and a subsequent reduction thereof resulted in increased beta cell proliferation (mean ± SEM vs control: 7.2 ± 0.4% vs 5.1 ± 0.5%). Chemical, transient induction of ER stress in vitro by ER-stress-inducing compounds reproduced this beta cell cycling response, as assessed by cumulative EdU labelling during a 3 day washout period (mean ± SEM vs control: 2.6 ± 0.4% vs 0.8 ± 0.2% for thapsigargin and 3.8 ± 0.9% vs 1.0 ± 0.2% for tunicamycin), which further increased under high-glucose conditions when islets were exposed to thapsigargin (mean ± SEM vs control: 9.0 ± 1.2% vs 2.0 ± 0.4%).CONCLUSIONS/INTERPRETATIONOur findings uncover a link between transgene (over)expression, ER stress, glucose and cell cycle activation in mouse beta cells.DATA AND CODE AVAILABILITYThe single-cell RNA-seq data generated in this study are deposited at GEO (NCBI) with accession code GSE274443.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"31 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971829","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}
AIMS/HYPOTHESISPhysical education (PE) in adolescents with type 1 diabetes remains underexplored despite its key role in shaping adolescents' engagement with physical activity. While the only available data about inclusion of individuals with type 1 diabetes in PE lessons are based on interviews with teachers, this study aimed to explore the first-person perspectives of adolescents.METHODSThis was a child-centred qualitative study using grounded theory. We conducted semi-structured interviews with 25 adolescents (11-15 years) with type 1 diabetes recruited from diverse middle schools.RESULTSStudents' experiences in PE are shaped by the balance between equal participation, recognition of diabetes-related needs and discreet support for autonomous glucose management, which together foster a psychologically healthy environment prompting competence, connection and autonomy. Fear of hypoglycaemia was not identified as a barrier to PE participation. Adolescents instead called for greater teacher support and regretted that excessive caution sometimes undermined their engagement and sense of competence. They sought equal participation without discrimination, with minimal adjustments for hypoglycaemic episodes. The practical constraints of insulin pumps further highlight the need for more discreet technological designs.CONCLUSIONS/INTERPRETATIONThe study emphasises teachers' central role and the need for education on self-regulating physical effort according to glucose levels, which remains underdeveloped. Practical recommendations are identified to better meet the needs of young people with type 1 diabetes in middle school PE.
{"title":"How adolescents with type 1 diabetes experience physical education in middle school: a qualitative study.","authors":"Isabelle Joing,Gaëlle Marais,Aurore Huchez,Elodie Lespagnol,Elsa Heyman","doi":"10.1007/s00125-025-06648-4","DOIUrl":"https://doi.org/10.1007/s00125-025-06648-4","url":null,"abstract":"AIMS/HYPOTHESISPhysical education (PE) in adolescents with type 1 diabetes remains underexplored despite its key role in shaping adolescents' engagement with physical activity. While the only available data about inclusion of individuals with type 1 diabetes in PE lessons are based on interviews with teachers, this study aimed to explore the first-person perspectives of adolescents.METHODSThis was a child-centred qualitative study using grounded theory. We conducted semi-structured interviews with 25 adolescents (11-15 years) with type 1 diabetes recruited from diverse middle schools.RESULTSStudents' experiences in PE are shaped by the balance between equal participation, recognition of diabetes-related needs and discreet support for autonomous glucose management, which together foster a psychologically healthy environment prompting competence, connection and autonomy. Fear of hypoglycaemia was not identified as a barrier to PE participation. Adolescents instead called for greater teacher support and regretted that excessive caution sometimes undermined their engagement and sense of competence. They sought equal participation without discrimination, with minimal adjustments for hypoglycaemic episodes. The practical constraints of insulin pumps further highlight the need for more discreet technological designs.CONCLUSIONS/INTERPRETATIONThe study emphasises teachers' central role and the need for education on self-regulating physical effort according to glucose levels, which remains underdeveloped. Practical recommendations are identified to better meet the needs of young people with type 1 diabetes in middle school PE.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"5 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907569","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}
Pub Date : 2026-01-07DOI: 10.1007/s00125-025-06645-7
Efraim Westholm,Alexandros Karagiannopoulos,Bibi U Nielsen,James A M Shaw,Anna Wendt,Daniel Faurholt-Jepsen,Lena Eliasson
AIMS/HYPOTHESISMicroRNAs are potential predictors and mediators of metabolic disease. Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity in cystic fibrosis (CF). Here we aimed to investigate serum microRNAs in individuals with CF and differing glucose tolerance status. Specifically, we hypothesised that the circulating microRNA profile varies depending on glucose tolerance status and can change rapidly in response to a glucose challenge in individuals with CF.METHODSWe studied a cohort of 93 adult Danish participants with CF from four glucose tolerance categories: normal glucose tolerance, indeterminate glucose tolerance, impaired glucose tolerance and CFRD. In a cross-sectional design we sampled during an OGTT at baseline, 10 min, 30 min, 60 min and 180 min. A total serum microRNA sequencing was performed using baseline and 60 min samples from 12 selected individuals, three from each category. We identified 16 candidate microRNAs, and these were further investigated in the full cohort at all OGTT timepoints using a locked nucleic acid reverse transcription quantitative PCR assay. Three microRNAs were selected for in-depth assessment including impact on insulin secretion.RESULTSWe identified four microRNAs differentially expressed at baseline (miR-34a-5p, miR-122-5p, miR-885-3 and miR-885-5p) and 12 with differential expression changes in response to glucose ingestion. Locked nucleic acid reverse transcription quantitative PCR assay validated the results of eight of these microRNAs and miR-34a-5p, miR-122-5p and miR-223-3p were selected for in-depth assessment. MiR-34a-5p and miR-122-5p were elevated at baseline in indeterminate glucose tolerance and CFRD and were associated with elevated liver damage markers. MiR-223-3p was differentially expressed during the OGTT, with different patterns depending on glucose tolerance state. Glucose-stimulated insulin secretion was increased after overexpression of miR-122-5p or miR-223-3p and cell viability was decreased after overexpression of miR-34a-5p in insulin-secreting cells.CONCLUSIONS/INTERPRETATIONMiR-34a-5p and miR-122-5p show potential as biomarkers for CFRD development and liver damage. MiR-122-5p and miR-223-3p could mitigate CFRD development by increasing the secretory capacity of the beta cells while miR-34a-5p might propagate CFRD development by reducing cell viability. We propose that circulating microRNAs can serve as biomarkers for CF complications. We further advocate that circulating microRNAs can play a part in the intricate crosstalk between metabolic organs and the endocrine pancreas in health and disease.
{"title":"Dynamic changes in circulating microRNAs during oral glucose tolerance testing support their potential as diagnostic and monitoring biomarkers in cystic fibrosis-related diabetes.","authors":"Efraim Westholm,Alexandros Karagiannopoulos,Bibi U Nielsen,James A M Shaw,Anna Wendt,Daniel Faurholt-Jepsen,Lena Eliasson","doi":"10.1007/s00125-025-06645-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06645-7","url":null,"abstract":"AIMS/HYPOTHESISMicroRNAs are potential predictors and mediators of metabolic disease. Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity in cystic fibrosis (CF). Here we aimed to investigate serum microRNAs in individuals with CF and differing glucose tolerance status. Specifically, we hypothesised that the circulating microRNA profile varies depending on glucose tolerance status and can change rapidly in response to a glucose challenge in individuals with CF.METHODSWe studied a cohort of 93 adult Danish participants with CF from four glucose tolerance categories: normal glucose tolerance, indeterminate glucose tolerance, impaired glucose tolerance and CFRD. In a cross-sectional design we sampled during an OGTT at baseline, 10 min, 30 min, 60 min and 180 min. A total serum microRNA sequencing was performed using baseline and 60 min samples from 12 selected individuals, three from each category. We identified 16 candidate microRNAs, and these were further investigated in the full cohort at all OGTT timepoints using a locked nucleic acid reverse transcription quantitative PCR assay. Three microRNAs were selected for in-depth assessment including impact on insulin secretion.RESULTSWe identified four microRNAs differentially expressed at baseline (miR-34a-5p, miR-122-5p, miR-885-3 and miR-885-5p) and 12 with differential expression changes in response to glucose ingestion. Locked nucleic acid reverse transcription quantitative PCR assay validated the results of eight of these microRNAs and miR-34a-5p, miR-122-5p and miR-223-3p were selected for in-depth assessment. MiR-34a-5p and miR-122-5p were elevated at baseline in indeterminate glucose tolerance and CFRD and were associated with elevated liver damage markers. MiR-223-3p was differentially expressed during the OGTT, with different patterns depending on glucose tolerance state. Glucose-stimulated insulin secretion was increased after overexpression of miR-122-5p or miR-223-3p and cell viability was decreased after overexpression of miR-34a-5p in insulin-secreting cells.CONCLUSIONS/INTERPRETATIONMiR-34a-5p and miR-122-5p show potential as biomarkers for CFRD development and liver damage. MiR-122-5p and miR-223-3p could mitigate CFRD development by increasing the secretory capacity of the beta cells while miR-34a-5p might propagate CFRD development by reducing cell viability. We propose that circulating microRNAs can serve as biomarkers for CF complications. We further advocate that circulating microRNAs can play a part in the intricate crosstalk between metabolic organs and the endocrine pancreas in health and disease.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"42 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907802","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}
Aims/hypothesis: Diabetes heterogeneity has been modelled as a continuum in European populations, but its phenotypes and long-term comorbidity risks remain unclear in Chinese individuals. This study aimed to identify distinct phenotypes and evaluate their links to future cardiometabolic risks in a large Chinese cohort.
Methods: The discriminative dimensionality reduction with trees (DDRTree) algorithm was used to develop a tree structure based on nine clinical variables. Cox proportional hazard models or logistic regression models were used to analyse probabilities of diabetes-related outcomes.
Results: This study included 19,612 individuals with newly diagnosed diabetes (36.8% male, mean age 59.01 years [SD 8.63]) from the China Cardiometabolic Disease and Cancer Cohort (4C) study. All nine clinical variables used for establishing DDRTree models were gradient distributed across the tree. By overlaying risks of diabetes-related outcomes, we show how these risks differ by participant phenotype. Participants characterised by hyperglycaemia, obesity and dyslipidaemia showed elevated risks of insulin initiation, hypoglycaemia and chronic kidney diseases, while those with hypertension and high creatinine, total cholesterol and alanine aminotransferase levels were associated with a higher risk of CVD. Notably, social determinants and lifestyle factors further contributed to the observed heterogeneity.
Conclusions/interpretation: These findings characterise the heterogeneity of diabetes phenotypes and complication risks in the Chinese population, suggesting potential implications for personalised diabetes care. Given the observed phenotypic differences, management strategies should consider population-specific characteristics.
{"title":"Heterogeneity of diabetes and disease progression with a tree-like representation: findings from the China Cardiometabolic Disease and Cancer Cohort (4C) study.","authors":"Xiaojing Jia, Shuangyuan Wang, Hong Lin, Yuanyue Zhu, Yilan Ding, Mian Li, Yu Xu, Min Xu, Feiyue Huang, Feixia Shen, Xuejiang Gu, Yiming Mu, Lulu Chen, Tianshu Zeng, Lixin Shi, Qing Su, Xuefeng Yu, Li Yan, Guijun Qin, Qin Wan, Gang Chen, Xulei Tang, Zhengnan Gao, Ruying Hu, Zuojie Luo, Yingfen Qin, Li Chen, Xinguo Hou, Yanan Huo, Qiang Li, Guixia Wang, Yinfei Zhang, Chao Liu, Youmin Wang, Shengli Wu, Tao Yang, Huacong Deng, Yifang Zhang, Huapeng Wei, Jie Zheng, Tiange Wang, Zhiyun Zhao, Jiajun Zhao, Guang Ning, Weiqing Wang, Yufang Bi, Jieli Lu","doi":"10.1007/s00125-025-06528-x","DOIUrl":"10.1007/s00125-025-06528-x","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Diabetes heterogeneity has been modelled as a continuum in European populations, but its phenotypes and long-term comorbidity risks remain unclear in Chinese individuals. This study aimed to identify distinct phenotypes and evaluate their links to future cardiometabolic risks in a large Chinese cohort.</p><p><strong>Methods: </strong>The discriminative dimensionality reduction with trees (DDRTree) algorithm was used to develop a tree structure based on nine clinical variables. Cox proportional hazard models or logistic regression models were used to analyse probabilities of diabetes-related outcomes.</p><p><strong>Results: </strong>This study included 19,612 individuals with newly diagnosed diabetes (36.8% male, mean age 59.01 years [SD 8.63]) from the China Cardiometabolic Disease and Cancer Cohort (4C) study. All nine clinical variables used for establishing DDRTree models were gradient distributed across the tree. By overlaying risks of diabetes-related outcomes, we show how these risks differ by participant phenotype. Participants characterised by hyperglycaemia, obesity and dyslipidaemia showed elevated risks of insulin initiation, hypoglycaemia and chronic kidney diseases, while those with hypertension and high creatinine, total cholesterol and alanine aminotransferase levels were associated with a higher risk of CVD. Notably, social determinants and lifestyle factors further contributed to the observed heterogeneity.</p><p><strong>Conclusions/interpretation: </strong>These findings characterise the heterogeneity of diabetes phenotypes and complication risks in the Chinese population, suggesting potential implications for personalised diabetes care. Given the observed phenotypic differences, management strategies should consider population-specific characteristics.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"114-126"},"PeriodicalIF":10.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12686024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946281","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}
Pub Date : 2026-01-01Epub Date: 2025-10-02DOI: 10.1007/s00125-025-06563-8
Dominika A Michalek, Courtney Tern, Catherine C Robertson, Wei-Min Chen, Suna Onengut-Gumuscu, Stephen S Rich
Aims/hypothesis: Type 1 diabetes is characterised by the destruction of pancreatic beta cells. Genetic factors account for approximately 50% of the total risk, with variants in the HLA region contributing to half of this genetic risk. Research has historically focused on populations of European ancestry. We developed HLA-focused type 1 diabetes genetic risk scores (T1D GRSHLA) using SNPs or HLA alleles from four ancestry groups (admixed African [AFR; T1D GRSHLA-AFR], admixed American [AMR; T1D GRSHLA-AMR], European [EUR; T1D GRSHLA-EUR] and Finnish [FIN; T1D GRSHLA-FIN]). We also developed an across-ancestry GRS (ALL; T1D GRSHLA-ALL). We assessed the performance of the GRS in each population to determine the transferability of constructed scores.
Methods: A total of 41,689 samples and 13,695 SNPs in the HLA region were genotyped, with HLA alleles imputed using the HLA-TAPAS multi-ethnic reference panel. Conditionally independent SNPs and HLA alleles associated with type 1 diabetes were identified in each population group to construct T1D GRSHLA models. Generated T1D GRSHLA models were used to predict HLA-focused type 1 diabetes genetic risk across four ancestry groups. The performance of each T1D GRSHLA model was assessed using receiver operating characteristic (ROC) AUCs, and compared statistically.
Results: Each T1D GRSHLA model included a different number of conditionally independent HLA-region SNPs (AFR, n=5; AMR, n=3; EUR, n=38; FIN, n=6; ALL, n=36) and HLA alleles (AFR, n=6; AMR, n=5; EUR, n=40; FIN, n=8; ALL, n=41). The ROC AUC values for the T1D GRSHLA from SNPs or HLA alleles were similar, and ranged from 0.73 (T1D GRSHLA-allele-AMR applied to FIN) to 0.88 (T1D GRSHLA-allele-EUR applied to EUR). The ROC AUC using the combined set of conditionally independent SNPs (T1D GRSHLA-SNP-ALL) or HLA alleles (T1D GRSHLA-allele-ALL) performed uniformly well across all ancestry groups, with values ranging from 0.82 to 0.88 for SNPs and 0.80 to 0.87 for HLA alleles.
Conclusions/interpretation: T1D GRSHLA models derived from SNPs performed equivalently to those derived from HLA alleles across ancestries. In addition, T1D GRSHLA-SNP-ALL and GRSHLA-allele-ALL models had consistently high ROC AUC values when applied across ancestry groups. Larger studies in more diverse populations are needed to better assess the transferability of T1D GRSHLA across ancestries.
{"title":"HLA-focused type 1 diabetes genetic risk prediction in populations of diverse ancestry.","authors":"Dominika A Michalek, Courtney Tern, Catherine C Robertson, Wei-Min Chen, Suna Onengut-Gumuscu, Stephen S Rich","doi":"10.1007/s00125-025-06563-8","DOIUrl":"10.1007/s00125-025-06563-8","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Type 1 diabetes is characterised by the destruction of pancreatic beta cells. Genetic factors account for approximately 50% of the total risk, with variants in the HLA region contributing to half of this genetic risk. Research has historically focused on populations of European ancestry. We developed HLA-focused type 1 diabetes genetic risk scores (T1D GRS<sub>HLA</sub>) using SNPs or HLA alleles from four ancestry groups (admixed African [AFR; T1D GRS<sub>HLA-AFR</sub>], admixed American [AMR; T1D GRS<sub>HLA-AMR</sub>], European [EUR; T1D GRS<sub>HLA-EUR</sub>] and Finnish [FIN; T1D GRS<sub>HLA-FIN</sub>]). We also developed an across-ancestry GRS (ALL; T1D GRS<sub>HLA-ALL</sub>). We assessed the performance of the GRS in each population to determine the transferability of constructed scores.</p><p><strong>Methods: </strong>A total of 41,689 samples and 13,695 SNPs in the HLA region were genotyped, with HLA alleles imputed using the HLA-TAPAS multi-ethnic reference panel. Conditionally independent SNPs and HLA alleles associated with type 1 diabetes were identified in each population group to construct T1D GRS<sub>HLA</sub> models. Generated T1D GRS<sub>HLA</sub> models were used to predict HLA-focused type 1 diabetes genetic risk across four ancestry groups. The performance of each T1D GRS<sub>HLA</sub> model was assessed using receiver operating characteristic (ROC) AUCs, and compared statistically.</p><p><strong>Results: </strong>Each T1D GRS<sub>HLA</sub> model included a different number of conditionally independent HLA-region SNPs (AFR, n=5; AMR, n=3; EUR, n=38; FIN, n=6; ALL, n=36) and HLA alleles (AFR, n=6; AMR, n=5; EUR, n=40; FIN, n=8; ALL, n=41). The ROC AUC values for the T1D GRS<sub>HLA</sub> from SNPs or HLA alleles were similar, and ranged from 0.73 (T1D GRS<sub>HLA-allele-AMR</sub> applied to FIN) to 0.88 (T1D GRS<sub>HLA-allele-EUR</sub> applied to EUR). The ROC AUC using the combined set of conditionally independent SNPs (T1D GRS<sub>HLA-SNP-ALL</sub>) or HLA alleles (T1D GRS<sub>HLA-allele-ALL</sub>) performed uniformly well across all ancestry groups, with values ranging from 0.82 to 0.88 for SNPs and 0.80 to 0.87 for HLA alleles.</p><p><strong>Conclusions/interpretation: </strong>T1D GRS<sub>HLA</sub> models derived from SNPs performed equivalently to those derived from HLA alleles across ancestries. In addition, T1D GRS<sub>HLA-SNP-ALL</sub> and GRS<sub>HLA-allele-ALL</sub> models had consistently high ROC AUC values when applied across ancestry groups. Larger studies in more diverse populations are needed to better assess the transferability of T1D GRS<sub>HLA</sub> across ancestries.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"146-156"},"PeriodicalIF":10.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12685975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205633","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}
Pub Date : 2026-01-01Epub Date: 2025-09-03DOI: 10.1007/s00125-025-06522-3
Marija Petkovic, Ermelindo C Leal, Anja E Sørensen, Per T Jørgensen, Jesper T Wengel, Rosa R Jersie-Christensen, Jesper T Troelsen, Eugenia Carvalho, Louise T Dalgaard
Aims/hypothesis: Upregulation of miR-146a-5p and miR-29-3p is observed in chronic non-healing wounds in diabetes. Their single or combined inhibition's molecular and cellular effects were assessed in human keratinocytes (HaCaT cells) and in vivo using a mouse model of type 1 diabetes.
Methods: As primary outcomes, we screened for proteome changes in HaCaT cells by LC-MS/MS after transfection with miR-146a-5p or miR-29a-3p inhibitors individually or in combination and following stimulation with TNF-α. Moreover, as a secondary outcome, we collected the data and cryopreserved and paraffin-embedded skin biopsies to estimate the tissue response to miRNA inhibition using immunofluorescence and histological analysis. Cryopreserved biopsies were also used for the LC-MS/MS proteome profiling to identify targets and cellular pathways involved in observed tissue changes.
Results: We identified a panel of extracellular matrix proteins, mainly laminins, whose levels changed after transfection with miR-146a-5p or miR-29a-3p inhibitors in HaCaT cells, counteracting TNF-α effects. There was a difference in wound closure rate in vivo between the dual inhibition of miR-146a-5p and miR-29a-3p and scramble controls on day 8 (p<0.01) and day 9 (p<0.05), although not at day 10. Histological analysis at day 10 shows a loose papillary layer in the scramble inhibition group, indicating incomplete wound closure compared with dual miRNA inhibition. Moreover, the dual action of the inhibitors decreased inflammation at day 3 and day 10 (both p<0.001) and reactive oxygen species formation (p<0.01) 3 days post wounding, while increasing the angiogenesis on day 3 (p<0.01) and day 10 (p<0.001). This was consistent with cytoskeletal rearrangements and collagen alterations observed in proteome profiling.
Conclusions/interpretation: These findings demonstrate that dual inhibition of miR-146a-5p and miR-29a-3p in vitro synergises in a bidirectional manner, resulting either in intermediate effects or in cancelling each other's activity for the levels of specific proteins of basal lamina that impair proliferation and cell motility, compared with the individual inhibitors. Topical supplementation of miR-146a-5p and miR-29a-3p inhibitors to diabetic mouse wounds resulted in a reduction in wound size on days 8 and 9, which correspond to the later stages of healing, but did not lead to complete healing by day 10. However, dual inhibition demonstrates favourable effects on high oxidative stress, elevated inflammation and poor angiogenesis. These effects are superior to single miRNA inhibition, suggesting that combined miRNA inhibition could be a promising therapeutic strategy for diabetic wound healing. Nevertheless, further studies in humans are warranted.
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