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.
{"title":"Improved wound healing by dual inhibition of miR-146a-5p and miR-29a-3p supports a network action of dysregulated miRNAs in diabetic skin.","authors":"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","doi":"10.1007/s00125-025-06522-3","DOIUrl":"10.1007/s00125-025-06522-3","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions/interpretation: </strong>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.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"214-229"},"PeriodicalIF":10.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12685990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946329","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 : 2025-12-26DOI: 10.1007/s00125-025-06642-w
Yue Yun, Yu-Dan Liu, Ze-Mian Yang, Yi-Qiao Wang, Nan Zhang, Wen-Jing Li, Di Gao, Lei Sha
{"title":"Duodenal myoelectrical hyperactivity drives diabetic remission in rat models of type 2 diabetes","authors":"Yue Yun, Yu-Dan Liu, Ze-Mian Yang, Yi-Qiao Wang, Nan Zhang, Wen-Jing Li, Di Gao, Lei Sha","doi":"10.1007/s00125-025-06642-w","DOIUrl":"https://doi.org/10.1007/s00125-025-06642-w","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"9 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836134","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 : 2025-12-26DOI: 10.1007/s00125-025-06638-6
Liam O’Reilly, Le May Thai, Nancy Sue, Rama Dhenni, Ariel Castro-Martinez, Marcia Munoz, Michael J. Rogers, Tri G. Phan, Carsten Schmitz-Peiffer, Katharine M. Irvine, Trevor J. Biden
{"title":"Acute and resolving inflammation differentially regulates beta cell function in mice via interactions between peritoneal and islet-associated macrophages","authors":"Liam O’Reilly, Le May Thai, Nancy Sue, Rama Dhenni, Ariel Castro-Martinez, Marcia Munoz, Michael J. Rogers, Tri G. Phan, Carsten Schmitz-Peiffer, Katharine M. Irvine, Trevor J. Biden","doi":"10.1007/s00125-025-06638-6","DOIUrl":"https://doi.org/10.1007/s00125-025-06638-6","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"77 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836132","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 : 2025-12-26DOI: 10.1007/s00125-025-06639-5
Yiqing Zhou, Yongchun Zeng, Yu Chen, Lei Zhang, Qianna Zhen, Yong Chen, Rui Cheng, Yan Wang, Qian Ge
{"title":"Phosphodiesterase ENPP2, which is co-upregulated in obese and pregnant mice, is essential for islet beta cell compensation during obesity","authors":"Yiqing Zhou, Yongchun Zeng, Yu Chen, Lei Zhang, Qianna Zhen, Yong Chen, Rui Cheng, Yan Wang, Qian Ge","doi":"10.1007/s00125-025-06639-5","DOIUrl":"https://doi.org/10.1007/s00125-025-06639-5","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"56 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836133","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 : 2025-12-24DOI: 10.1007/s00125-025-06633-x
Vanderlei C Bertuol,Fernando Iorra,Tarsila Vieceli,Nicole T Tonolli,Roberta Zappelini,Luiza van der Sand,Cristiane B Leitão,Dimitris V Rados
AIMS/HYPOTHESISInsulin therapy is essential for managing hyperglycaemia in type 2 diabetes mellitus when oral or non-insulin injectable agents are no longer effective. However, the comparative effectiveness and safety of different insulin regimens remain uncertain. We aimed to compare the effects of basal, basal-bolus, biphasic and prandial insulin regimens on glycaemic management, weight, severe hypoglycaemia, insulin dose and quality of life in adults with type 2 diabetes.METHODSWe conducted a systematic review and network meta-analysis of RCTs. PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov were searched through to September 2025. The inclusion criteria for studies were RCTs enrolling adults with type 2 diabetes that compared at least two of the specified insulin regimens over ≥12 weeks. Pairs of reviewers independently screened studies, extracted data and assessed risk of bias using the Cochrane RoB-2 tool. Network meta-analyses were performed using a frequentist random-effects model, with basal insulin as the reference.RESULTSFifty-eight RCTs involving 19,122 participants were included. Compared with basal insulin, HbA1c reduction was -3.4 mmol/mol (95% CI -4.9, -1.9 mmol/mol) (-0.31% [95% CI -0.45%, -0.17%]) with a basal-bolus insulin regimen, -2.7 mmol/mol (95% CI -3.7, -1.6 mmol/mol) (-0.24% [95% CI -0.34%, -0.15%]) with biphasic insulin and -4.1 mmol/mol (95% CI -6.2, -2.1 mmol/mol) (-0.38% [95% CI -0.57%, -0.19%]) with prandial insulin. These results were classified as being of moderate confidence due to incoherence. All regimens were associated with approximately 30% increased probability of achieving HbA1c target, 1 kg greater weight gain, and a borderline increase in the risk of severe hypoglycaemia. Insulin doses were slightly higher with basal-bolus and biphasic regimens. Quality-of-life data were limited. Subgroup analyses for insulin initiation and intensification yielded consistent results.CONCLUSIONS/INTERPRETATIONComplex insulin regimens provide modest glycaemic benefits over basal insulin but are associated with greater weight gain and a suggested higher risk of hypoglycaemia. These results are based on evidence of moderate confidence. These trade-offs support the need for individualised regimen selection, informed by clinical context, patient preferences and treatment goals.TRIAL REGISTRATIONPROSPERO registration no. CRD42020181473.FUNDINGThis research was supported by the Committee for the Development of Higher Education Personnel (CAPES) and the Hospital de Clínicas de Porto Alegre - FIPE HCPA.
目的/假设当口服或非胰岛素注射药物不再有效时，胰岛素治疗对于控制2型糖尿病患者的高血糖是必不可少的。然而，不同胰岛素治疗方案的相对有效性和安全性仍不确定。我们的目的是比较基础胰岛素、基础胰岛素、双期胰岛素和餐后胰岛素治疗方案对成人2型糖尿病患者血糖管理、体重、严重低血糖、胰岛素剂量和生活质量的影响。方法对随机对照试验进行系统评价和网络荟萃分析。PubMed、EMBASE、Cochrane图书馆和ClinicalTrials.gov的检索截止到2025年9月。研究的纳入标准是纳入成人2型糖尿病患者的随机对照试验，并在≥12周的时间内比较至少两种指定的胰岛素方案。对审稿人独立筛选研究、提取数据并使用Cochrane rob2工具评估偏倚风险。网络荟萃分析采用频率随机效应模型，以基础胰岛素为参考。结果共纳入58项随机对照试验，共19122名受试者。与基础胰岛素相比，基础胰岛素方案的HbA1c降低值为-3.4 mmol/mol (95% CI -4.9, -1.9 mmol/mol) (-0.31% [95% CI -0.45%, -0.17%])，双相胰岛素方案的HbA1c降低值为-2.7 mmol/mol (95% CI -3.7, -1.6 mmol/mol) (-0.24% [95% CI -0.34%, -0.15%])，餐用胰岛素方案的HbA1c降低值为-4.1 mmol/mol (95% CI -6.2, -2.1 mmol/mol) （-0.38% [95% CI -0.57%, -0.19%]）。由于不连贯，这些结果被归类为中等置信度。所有方案均与实现HbA1c目标的可能性增加约30%、体重增加1公斤以及严重低血糖风险的临界增加相关。基础丸和双期方案的胰岛素剂量略高。生活质量数据有限。胰岛素起始和强化的亚组分析结果一致。结论/解释：与基础胰岛素相比，复合胰岛素方案提供了适度的降糖益处，但与更大的体重增加和更高的低血糖风险相关。这些结果是基于中等可信度的证据。这些权衡支持了根据临床情况、患者偏好和治疗目标进行个性化方案选择的必要性。试用注册号普洛斯彼罗注册号CRD42020181473。本研究得到了高等教育人员发展委员会（CAPES）和阿雷格里港医院Clínicas - FIPE HCPA的支持。
{"title":"Effects of insulin regimens for type 2 diabetes mellitus: a systematic review and network meta-analysis.","authors":"Vanderlei C Bertuol,Fernando Iorra,Tarsila Vieceli,Nicole T Tonolli,Roberta Zappelini,Luiza van der Sand,Cristiane B Leitão,Dimitris V Rados","doi":"10.1007/s00125-025-06633-x","DOIUrl":"https://doi.org/10.1007/s00125-025-06633-x","url":null,"abstract":"AIMS/HYPOTHESISInsulin therapy is essential for managing hyperglycaemia in type 2 diabetes mellitus when oral or non-insulin injectable agents are no longer effective. However, the comparative effectiveness and safety of different insulin regimens remain uncertain. We aimed to compare the effects of basal, basal-bolus, biphasic and prandial insulin regimens on glycaemic management, weight, severe hypoglycaemia, insulin dose and quality of life in adults with type 2 diabetes.METHODSWe conducted a systematic review and network meta-analysis of RCTs. PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov were searched through to September 2025. The inclusion criteria for studies were RCTs enrolling adults with type 2 diabetes that compared at least two of the specified insulin regimens over ≥12 weeks. Pairs of reviewers independently screened studies, extracted data and assessed risk of bias using the Cochrane RoB-2 tool. Network meta-analyses were performed using a frequentist random-effects model, with basal insulin as the reference.RESULTSFifty-eight RCTs involving 19,122 participants were included. Compared with basal insulin, HbA1c reduction was -3.4 mmol/mol (95% CI -4.9, -1.9 mmol/mol) (-0.31% [95% CI -0.45%, -0.17%]) with a basal-bolus insulin regimen, -2.7 mmol/mol (95% CI -3.7, -1.6 mmol/mol) (-0.24% [95% CI -0.34%, -0.15%]) with biphasic insulin and -4.1 mmol/mol (95% CI -6.2, -2.1 mmol/mol) (-0.38% [95% CI -0.57%, -0.19%]) with prandial insulin. These results were classified as being of moderate confidence due to incoherence. All regimens were associated with approximately 30% increased probability of achieving HbA1c target, 1 kg greater weight gain, and a borderline increase in the risk of severe hypoglycaemia. Insulin doses were slightly higher with basal-bolus and biphasic regimens. Quality-of-life data were limited. Subgroup analyses for insulin initiation and intensification yielded consistent results.CONCLUSIONS/INTERPRETATIONComplex insulin regimens provide modest glycaemic benefits over basal insulin but are associated with greater weight gain and a suggested higher risk of hypoglycaemia. These results are based on evidence of moderate confidence. These trade-offs support the need for individualised regimen selection, informed by clinical context, patient preferences and treatment goals.TRIAL REGISTRATIONPROSPERO registration no. CRD42020181473.FUNDINGThis research was supported by the Committee for the Development of Higher Education Personnel (CAPES) and the Hospital de Clínicas de Porto Alegre - FIPE HCPA.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"59 6 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813504","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 : 2025-12-22DOI: 10.1007/s00125-025-06622-0
Heather C Denroche,Victoria Ng,Jane Velghe,Imelda Suen,Liam Stanley,Dominika Nackiewicz,Mitsuhiro Komba,Derek L Dai,Galina Soukhatcheva,Sam Chen,C Bruce Verchere
AIMS/HYPOTHESISIslet amyloid contributes to beta cell failure in type 2 diabetes through several mechanisms, one being the potent induction of local islet inflammation through activating inflammatory pathways in islet macrophages. As islet amyloid has recently been reported in pancreases of people with type 1 diabetes, and islet macrophages are thought to play a role in the pathogenesis of type 1 diabetes, we sought to understand the impact of islet amyloid on islet macrophages and beta cell autoimmunity.METHODSWe performed an unbiased phenotypic investigation of islet macrophages in the early stage of islet amyloid formation using single-cell RNA-seq of resident islet macrophages in mice with and without the amyloidogenic form of human islet amyloid polypeptide (hIAPP). The role of islet amyloid in autoimmune diabetes and antigen presentation was assessed in hIAPP-expressing NOD mice and in antigen-presenting cells ex vivo.RESULTSMHC class II (MHCII) antigen presentation genes were strongly downregulated in islet macrophages during islet amyloid formation. NOD mice expressing an hIAPP transgene had delayed diabetes relative to littermate controls (median onset 30.3 vs 19.5 weeks, p=0.016). Likewise, physiological expression of hIAPP by genetic knockin also delayed diabetes in NOD mice relative to littermate controls (median onset 28.2 vs 18.0 weeks, p=0.049), corresponding with decreased markers of antigen presentation and activation, as well as decreased immune cell infiltration in islets. Adoptive transfer studies showed that systemic autoimmune function remained intact and beta cells from hIAPP transgenic mice did not evade immune recognition by diabetogenic T cells, collectively indicating the protection from diabetes was mediated by decreased antigen presentation in the pancreas. Consistent with this, incubation of dendritic cells with islet amyloid polypeptide (IAPP) aggregates decreased MHCII surface expression and diminished antigen-specific T cell activation through a phagocytosis-dependent mechanism.CONCLUSIONS/INTERPRETATIONCollectively, our data reveal a novel role for IAPP aggregates in decreasing MHCII antigen presentation and show that despite the well-established proinflammatory response of macrophages to IAPP aggregates, the uptake of IAPP aggregates during early amyloid formation also disrupts beta cell autoimmunity and delays diabetes in NOD mice.
{"title":"Islet amyloid disrupts MHC class II antigen presentation and delays autoimmune diabetes in NOD mice.","authors":"Heather C Denroche,Victoria Ng,Jane Velghe,Imelda Suen,Liam Stanley,Dominika Nackiewicz,Mitsuhiro Komba,Derek L Dai,Galina Soukhatcheva,Sam Chen,C Bruce Verchere","doi":"10.1007/s00125-025-06622-0","DOIUrl":"https://doi.org/10.1007/s00125-025-06622-0","url":null,"abstract":"AIMS/HYPOTHESISIslet amyloid contributes to beta cell failure in type 2 diabetes through several mechanisms, one being the potent induction of local islet inflammation through activating inflammatory pathways in islet macrophages. As islet amyloid has recently been reported in pancreases of people with type 1 diabetes, and islet macrophages are thought to play a role in the pathogenesis of type 1 diabetes, we sought to understand the impact of islet amyloid on islet macrophages and beta cell autoimmunity.METHODSWe performed an unbiased phenotypic investigation of islet macrophages in the early stage of islet amyloid formation using single-cell RNA-seq of resident islet macrophages in mice with and without the amyloidogenic form of human islet amyloid polypeptide (hIAPP). The role of islet amyloid in autoimmune diabetes and antigen presentation was assessed in hIAPP-expressing NOD mice and in antigen-presenting cells ex vivo.RESULTSMHC class II (MHCII) antigen presentation genes were strongly downregulated in islet macrophages during islet amyloid formation. NOD mice expressing an hIAPP transgene had delayed diabetes relative to littermate controls (median onset 30.3 vs 19.5 weeks, p=0.016). Likewise, physiological expression of hIAPP by genetic knockin also delayed diabetes in NOD mice relative to littermate controls (median onset 28.2 vs 18.0 weeks, p=0.049), corresponding with decreased markers of antigen presentation and activation, as well as decreased immune cell infiltration in islets. Adoptive transfer studies showed that systemic autoimmune function remained intact and beta cells from hIAPP transgenic mice did not evade immune recognition by diabetogenic T cells, collectively indicating the protection from diabetes was mediated by decreased antigen presentation in the pancreas. Consistent with this, incubation of dendritic cells with islet amyloid polypeptide (IAPP) aggregates decreased MHCII surface expression and diminished antigen-specific T cell activation through a phagocytosis-dependent mechanism.CONCLUSIONS/INTERPRETATIONCollectively, our data reveal a novel role for IAPP aggregates in decreasing MHCII antigen presentation and show that despite the well-established proinflammatory response of macrophages to IAPP aggregates, the uptake of IAPP aggregates during early amyloid formation also disrupts beta cell autoimmunity and delays diabetes in NOD mice.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"1 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801339","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 : 2025-12-21DOI: 10.1007/s00125-025-06624-y
Courtney Claussen, Emily Papadimos, Dianna J. Magliano, Cheri Hotu, Hiliary Monteith, Baiju Shah, Louise Maple-Brown, Alex Brown, Odette Pearson, Donald Warne, Melanie Nadeau, Elizabeth L. M. Barr, Anthony J. Hanley
{"title":"Prevalence of type 2 diabetes among global Indigenous adult populations: a systematic review","authors":"Courtney Claussen, Emily Papadimos, Dianna J. Magliano, Cheri Hotu, Hiliary Monteith, Baiju Shah, Louise Maple-Brown, Alex Brown, Odette Pearson, Donald Warne, Melanie Nadeau, Elizabeth L. M. Barr, Anthony J. Hanley","doi":"10.1007/s00125-025-06624-y","DOIUrl":"https://doi.org/10.1007/s00125-025-06624-y","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"46 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796074","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 : 2025-12-21DOI: 10.1007/s00125-025-06634-w
Rebecca E. Dewhurst-Trigg, Jocelyn Atkins, Noel G. Morgan, Martin Eichmann, Sarah J. Richardson, Chloe L. Rackham
Aims/hypothesis Culture-expanded mesenchymal stromal cells (MSCs) reduce immune cell activation and improve islet functional survival. However, little is known about human pancreatic MSCs (pMSCs) in health or how they are altered in type 1 diabetes. Here, we determined the number, density and islet-protective phenotype of pMSCs in situ in individuals with and without type 1 diabetes. Methods Multiplex immunohistochemistry was used to identify pMSCs (CD90 <jats:sup>+</jats:sup> /CD105 <jats:sup>+</jats:sup> /CD73 <jats:sup>+</jats:sup> /CD31 <jats:sup>−</jats:sup> /CD45 <jats:sup>−</jats:sup> /CD34 <jats:sup>−</jats:sup> ) in human pancreas sections from 38 donors (Network for Pancreatic Organ Donors with Diabetes and Exeter Archival Diabetes Biobank). Donors were categorised as either <13 years at type 1 diabetes diagnosis ( <jats:italic>n</jats:italic> =8) or ≥13 years at type 1 diabetes diagnosis ( <jats:italic>n</jats:italic> =11) or were sex-matched individuals of similar age without diabetes. Consecutive sections were immunostained with antisera against insulin, glucagon and the established islet-protective and immunomodulatory factors annexin A1 (ANXA1) and indoleamine 2,3-dioxygenase 1. Whole-slide scans were acquired and pMSCs either inside or at the periphery (within 10 µm) of islets were quantified on an individual-islet basis. We identified 53,375 pMSCs and performed an analysis of 26,376 individual islets. Culture-expanded MSCs were exposed to cytokines and viability and proliferation were assessed by flow cytometry. Results pMSCs were identified in situ in the human pancreas where they wrap around the islet periphery in an expected spindle-like morphology. ANXA1 was expressed by 33.2% of pMSCs and was expressed constitutively among individuals with or without diabetes. The density of both intraislet pMSCs and pMSCs within 10 µm of the islet periphery was increased for insulin-containing islets in individuals with type 1 diabetes compared with individuals without diabetes ( <jats:italic>p</jats:italic> <0.001). pMSC density within 10 µm of the islet periphery was preferentially increased in individuals ≥13 years at type 1 diabetes diagnosis compared with individuals <13 years at type 1 diabetes diagnosis ( <jats:italic>p</jats:italic> <0.001). pMSC density was reduced around insulin-deficient islets compared with insulin-containing islets in individuals with diabetes ( <jats:italic>p</jats:italic> <0.001), consistent with an islet-protective role for pMSCs. Exposure of culture-expanded MSCs to an aggressive cytokine combination led to increased cell death and reduced proliferation. Conclusions/interpretation pMSCs express ANXA1 constitutively, suggesting an islet-protective role in health. The density of pMSCs was increased around insulin-containing islets and lost around insulin-deficient islets in individuals with type 1 diabetes which aligns with this hypothesis. pMSC density at the periphery of insulin-containing is
{"title":"Characterisation of human pancreatic mesenchymal stromal cells in type 1 diabetes","authors":"Rebecca E. Dewhurst-Trigg, Jocelyn Atkins, Noel G. Morgan, Martin Eichmann, Sarah J. Richardson, Chloe L. Rackham","doi":"10.1007/s00125-025-06634-w","DOIUrl":"https://doi.org/10.1007/s00125-025-06634-w","url":null,"abstract":"Aims/hypothesis Culture-expanded mesenchymal stromal cells (MSCs) reduce immune cell activation and improve islet functional survival. However, little is known about human pancreatic MSCs (pMSCs) in health or how they are altered in type 1 diabetes. Here, we determined the number, density and islet-protective phenotype of pMSCs in situ in individuals with and without type 1 diabetes. Methods Multiplex immunohistochemistry was used to identify pMSCs (CD90 <jats:sup>+</jats:sup> /CD105 <jats:sup>+</jats:sup> /CD73 <jats:sup>+</jats:sup> /CD31 <jats:sup>−</jats:sup> /CD45 <jats:sup>−</jats:sup> /CD34 <jats:sup>−</jats:sup> ) in human pancreas sections from 38 donors (Network for Pancreatic Organ Donors with Diabetes and Exeter Archival Diabetes Biobank). Donors were categorised as either <13 years at type 1 diabetes diagnosis ( <jats:italic>n</jats:italic> =8) or ≥13 years at type 1 diabetes diagnosis ( <jats:italic>n</jats:italic> =11) or were sex-matched individuals of similar age without diabetes. Consecutive sections were immunostained with antisera against insulin, glucagon and the established islet-protective and immunomodulatory factors annexin A1 (ANXA1) and indoleamine 2,3-dioxygenase 1. Whole-slide scans were acquired and pMSCs either inside or at the periphery (within 10 µm) of islets were quantified on an individual-islet basis. We identified 53,375 pMSCs and performed an analysis of 26,376 individual islets. Culture-expanded MSCs were exposed to cytokines and viability and proliferation were assessed by flow cytometry. Results pMSCs were identified in situ in the human pancreas where they wrap around the islet periphery in an expected spindle-like morphology. ANXA1 was expressed by 33.2% of pMSCs and was expressed constitutively among individuals with or without diabetes. The density of both intraislet pMSCs and pMSCs within 10 µm of the islet periphery was increased for insulin-containing islets in individuals with type 1 diabetes compared with individuals without diabetes ( <jats:italic>p</jats:italic> <0.001). pMSC density within 10 µm of the islet periphery was preferentially increased in individuals ≥13 years at type 1 diabetes diagnosis compared with individuals <13 years at type 1 diabetes diagnosis ( <jats:italic>p</jats:italic> <0.001). pMSC density was reduced around insulin-deficient islets compared with insulin-containing islets in individuals with diabetes ( <jats:italic>p</jats:italic> <0.001), consistent with an islet-protective role for pMSCs. Exposure of culture-expanded MSCs to an aggressive cytokine combination led to increased cell death and reduced proliferation. Conclusions/interpretation pMSCs express ANXA1 constitutively, suggesting an islet-protective role in health. The density of pMSCs was increased around insulin-containing islets and lost around insulin-deficient islets in individuals with type 1 diabetes which aligns with this hypothesis. pMSC density at the periphery of insulin-containing is","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"10 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796075","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 : 2025-12-19DOI: 10.1007/s00125-025-06637-7
João Sérgio Neves,Ana Rita Leite,Catarina Vale,Pedro Marques,Francisco Vasques-Nóvoa,Adelino Leite-Moreira,João Pedro Ferreira
AIMS/HYPOTHESISSimultaneous control of HbA1c, lipid profile, BP and body weight is essential for preventing chronic complications of type 2 diabetes. Glucagon-like peptide-1 (GLP-1)-based therapies improve all these variables but whether the dual GLP-1 / glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide is superior to semaglutide in attaining therapeutic targets remains unclear.METHODSWe performed a post hoc analysis of the SURPASS-2 trial, a randomised phase 3 study including 1879 adults with type 2 diabetes. Participants were randomised to receive tirzepatide (5, 10 or 15 mg) or semaglutide (1 mg). In this analysis, we compared the effects of tirzepatide vs semaglutide on the attainment of standard (HbA1c <53 mmol/mol [7%], BP <140/90 mmHg, LDL-cholesterol <1.8 mmol/l, >10% weight loss) and intensive (HbA1c <48 mmol/mol [6.5%], BP <130/80 mmHg, LDL-cholesterol <1.4 mmol/l , >15% weight loss) therapeutic targets at 40 weeks.RESULTSIn the SURPASS-2 trial, at baseline, 19% of participants were on target for attaining no standard goals, 59% for one goal and 21% for two or more goals. For intensive therapeutic targets, 58% of participants were on target for attaining zero goals, 38% for one goal and 4% for two goals. All doses of tirzepatide increased the number of achieved standard and intensive targets compared with semaglutide. For standard targets, 34% of participants treated with semaglutide met three or more targets, compared with 42%, 53% and 57% with tirzepatide 5, 10 and 15 mg, respectively. For intensive targets, 8% of participants treated with semaglutide met three or more targets, vs 15%, 20% and 29% with tirzepatide. Regarding specific therapeutic goals, tirzepatide increased the odds of achieving standard and intensive targets for HbA1c (HbA1c <53 mmol/mol [7%], OR 1.50 [95% CI 1.12, 2.00]; HbA1c <48 mmol/mol [6.5%], OR 1.88 [95%CI 1.49, 2.36]) and weight loss (weight loss >10%, OR 2.72 [95% CI 2.14, 3.47]; weight loss >15%, OR 3.86 [95% CI 2.69, 5.55]) and the intensive target for BP (OR 1.45 [95% CI 1.17, 1.81]).CONCLUSIONS/INTERPRETATIONTirzepatide improves therapeutic target attainment compared with semaglutide in type 2 diabetes. Longer trials are needed to confirm benefits on long-term prognosis.DATA AVAILABILITYData for this post hoc analysis was accessed through the Vivli (Center for Global Clinical Research Data) platform ( https://vivli.org ) with the Vivli ID 00009964.
目的/假设同时控制HbA1c、血脂、血压和体重对于预防2型糖尿病的慢性并发症至关重要。以胰高血糖素样肽-1 （GLP-1）为基础的治疗改善了所有这些变量，但GLP-1 /葡萄糖依赖性胰岛素多肽（GIP）激动剂替西帕肽在达到治疗目标方面是否优于半马鲁肽尚不清楚。方法：我们对SURPASS-2试验进行了事后分析，该试验是一项包括1879名2型糖尿病成人患者的随机3期研究。参与者随机接受替西帕肽（5、10或15毫克）或西马鲁肽（1毫克）治疗。在这项分析中，我们比较了替西帕肽和西马鲁肽在40周时达到标准（HbA1c减轻10%体重）和强化（HbA1c减轻15%体重）治疗目标的效果。结果在SURPASS-2试验中，在基线时，19%的参与者没有达到标准目标，59%达到一个目标，21%达到两个或更多目标。对于强化治疗目标，58%的参与者达到了零目标，38%达到了一个目标，4%达到了两个目标。与西马鲁肽相比，所有剂量的替西帕肽都增加了达到标准和强化目标的数量。对于标准目标，接受西马鲁肽治疗的参与者中有34%达到了三个或更多的目标，而接受替西帕肽5、10和15mg治疗的参与者分别为42%、53%和57%。对于强化靶标，8%的接受西马鲁肽治疗的受试者达到三个或更多靶标，而接受替西帕肽治疗的受试者达到15%、20%和29%。关于特定的治疗目标，替西帕肽增加了HbA1c标准和强化目标（HbA1c 10%, OR 2.72 [95% CI 2.14, 3.47]；体重减轻15%，OR 3.86 [95% CI 2.69, 5.55]）和BP强化目标（OR 1.45 [95% CI 1.17, 1.81]）的实现几率。结论/解释：与西马鲁肽相比，替西帕肽可提高2型糖尿病患者的治疗目标。需要更长时间的试验来证实对长期预后的益处。数据可用性通过Vivli（全球临床研究数据中心）平台（https://vivli.org）访问该事后分析的数据，Vivli ID为00009964。
{"title":"Efficacy of tirzepatide versus semaglutide in achieving therapeutic targets in type 2 diabetes: a post hoc analysis of the SURPASS-2 Trial.","authors":"João Sérgio Neves,Ana Rita Leite,Catarina Vale,Pedro Marques,Francisco Vasques-Nóvoa,Adelino Leite-Moreira,João Pedro Ferreira","doi":"10.1007/s00125-025-06637-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06637-7","url":null,"abstract":"AIMS/HYPOTHESISSimultaneous control of HbA1c, lipid profile, BP and body weight is essential for preventing chronic complications of type 2 diabetes. Glucagon-like peptide-1 (GLP-1)-based therapies improve all these variables but whether the dual GLP-1 / glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide is superior to semaglutide in attaining therapeutic targets remains unclear.METHODSWe performed a post hoc analysis of the SURPASS-2 trial, a randomised phase 3 study including 1879 adults with type 2 diabetes. Participants were randomised to receive tirzepatide (5, 10 or 15 mg) or semaglutide (1 mg). In this analysis, we compared the effects of tirzepatide vs semaglutide on the attainment of standard (HbA1c <53 mmol/mol [7%], BP <140/90 mmHg, LDL-cholesterol <1.8 mmol/l, >10% weight loss) and intensive (HbA1c <48 mmol/mol [6.5%], BP <130/80 mmHg, LDL-cholesterol <1.4 mmol/l , >15% weight loss) therapeutic targets at 40 weeks.RESULTSIn the SURPASS-2 trial, at baseline, 19% of participants were on target for attaining no standard goals, 59% for one goal and 21% for two or more goals. For intensive therapeutic targets, 58% of participants were on target for attaining zero goals, 38% for one goal and 4% for two goals. All doses of tirzepatide increased the number of achieved standard and intensive targets compared with semaglutide. For standard targets, 34% of participants treated with semaglutide met three or more targets, compared with 42%, 53% and 57% with tirzepatide 5, 10 and 15 mg, respectively. For intensive targets, 8% of participants treated with semaglutide met three or more targets, vs 15%, 20% and 29% with tirzepatide. Regarding specific therapeutic goals, tirzepatide increased the odds of achieving standard and intensive targets for HbA1c (HbA1c <53 mmol/mol [7%], OR 1.50 [95% CI 1.12, 2.00]; HbA1c <48 mmol/mol [6.5%], OR 1.88 [95%CI 1.49, 2.36]) and weight loss (weight loss >10%, OR 2.72 [95% CI 2.14, 3.47]; weight loss >15%, OR 3.86 [95% CI 2.69, 5.55]) and the intensive target for BP (OR 1.45 [95% CI 1.17, 1.81]).CONCLUSIONS/INTERPRETATIONTirzepatide improves therapeutic target attainment compared with semaglutide in type 2 diabetes. Longer trials are needed to confirm benefits on long-term prognosis.DATA AVAILABILITYData for this post hoc analysis was accessed through the Vivli (Center for Global Clinical Research Data) platform ( https://vivli.org ) with the Vivli ID 00009964.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"29 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785767","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 : 2025-12-19DOI: 10.1007/s00125-025-06635-9
Markus Mattila,Peppi Haario,Leena Hakola,Hanna-Mari Takkinen,Essi J Peltonen,Tuuli E Korhonen,Suvi Ahonen,Jorma Ilonen,Jorma Toppari,Mikael Knip,Riitta Veijola,Sari Niinistö,Suvi M Virtanen
AIMS/HYPOTHESISIn this prospective birth cohort study, we examined whether the dietary intake of A, B, C, D and E vitamins is associated with the risk of islet autoimmunity or type 1 diabetes in children who are genetically at risk for type 1 diabetes.METHODSData on vitamin intakes in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) cohort study were available for 5674 children born between September 1996 and September 2004 in Oulu University Hospital or Tampere University Hospital. Diet was assessed using 3-day food records at the age of 3 and 6 months, and annually from 1 to 6 years. The primary outcomes were: (1) islet autoimmunity defined as repeated positivity for islet cell autoantibodies and at least one out of three type 1 diabetes-related biochemical autoantibodies or a diagnosis of type 1 diabetes; and (2) a diagnosis of type 1 diabetes.RESULTSDuring the 6-year follow-up, 247 children (4.4%) developed islet autoimmunity and 94 (1.7%) developed type 1 diabetes. When adjusted for total energy intake, sex, HLA genotype and family history of diabetes, the intakes of retinol (HR 0.91; 95% credible interval [CrI] 0.86, 0.97 per 10 µg/MJ increase in intake), vitamin C (HR 0.70; 95% CrI 0.54, 0.90 per 10 µg/MJ) and vitamin E (HR 0.93; 95% CrI 0.89, 0.97 per 0.1 mg/MJ) were associated with decreased risk of islet autoimmunity and also with the risk of type 1 diabetes (retinol: HR 0.83; 95% CrI 0.74, 0.96 per 10 µg/MJ; vitamin C: HR 0.45; 95% CrI 0.23, 0.84 per 10 µg/MJ; vitamin E: HR 0.89; 95% CrI 0.80, 0.99 per 0.1 mg/MJ). The associations remained statistically significant after multiple testing correction for the risk of islet autoimmunity but not for type 1 diabetes. The association between retinol intake and islet autoimmunity risk was not significant when the 3-month age point, during which the child is primarily breastfed, was excluded. We observed a weak inverse association for vitamin D and islet autoimmunity, and no associations for B vitamins.CONCLUSIONS/INTERPRETATIONHigh intake of vitamin C and vitamin E was associated with a decreased risk of islet autoimmunity.
{"title":"Dietary intake of vitamins A, B, C, D and E and risk of islet autoimmunity and type 1 diabetes in genetically at-risk children: a prospective study from the DIPP birth cohort.","authors":"Markus Mattila,Peppi Haario,Leena Hakola,Hanna-Mari Takkinen,Essi J Peltonen,Tuuli E Korhonen,Suvi Ahonen,Jorma Ilonen,Jorma Toppari,Mikael Knip,Riitta Veijola,Sari Niinistö,Suvi M Virtanen","doi":"10.1007/s00125-025-06635-9","DOIUrl":"https://doi.org/10.1007/s00125-025-06635-9","url":null,"abstract":"AIMS/HYPOTHESISIn this prospective birth cohort study, we examined whether the dietary intake of A, B, C, D and E vitamins is associated with the risk of islet autoimmunity or type 1 diabetes in children who are genetically at risk for type 1 diabetes.METHODSData on vitamin intakes in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) cohort study were available for 5674 children born between September 1996 and September 2004 in Oulu University Hospital or Tampere University Hospital. Diet was assessed using 3-day food records at the age of 3 and 6 months, and annually from 1 to 6 years. The primary outcomes were: (1) islet autoimmunity defined as repeated positivity for islet cell autoantibodies and at least one out of three type 1 diabetes-related biochemical autoantibodies or a diagnosis of type 1 diabetes; and (2) a diagnosis of type 1 diabetes.RESULTSDuring the 6-year follow-up, 247 children (4.4%) developed islet autoimmunity and 94 (1.7%) developed type 1 diabetes. When adjusted for total energy intake, sex, HLA genotype and family history of diabetes, the intakes of retinol (HR 0.91; 95% credible interval [CrI] 0.86, 0.97 per 10 µg/MJ increase in intake), vitamin C (HR 0.70; 95% CrI 0.54, 0.90 per 10 µg/MJ) and vitamin E (HR 0.93; 95% CrI 0.89, 0.97 per 0.1 mg/MJ) were associated with decreased risk of islet autoimmunity and also with the risk of type 1 diabetes (retinol: HR 0.83; 95% CrI 0.74, 0.96 per 10 µg/MJ; vitamin C: HR 0.45; 95% CrI 0.23, 0.84 per 10 µg/MJ; vitamin E: HR 0.89; 95% CrI 0.80, 0.99 per 0.1 mg/MJ). The associations remained statistically significant after multiple testing correction for the risk of islet autoimmunity but not for type 1 diabetes. The association between retinol intake and islet autoimmunity risk was not significant when the 3-month age point, during which the child is primarily breastfed, was excluded. We observed a weak inverse association for vitamin D and islet autoimmunity, and no associations for B vitamins.CONCLUSIONS/INTERPRETATIONHigh intake of vitamin C and vitamin E was associated with a decreased risk of islet autoimmunity.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"21 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777436","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号