Islets最新文献

{"title":"Differential expression of mitomiRs in pancreatic islet cells associated with maternal protein restriction.","authors":"Cecile Jacovetti, Romano Regazzi","doi":"10.1080/19382014.2025.2610590","DOIUrl":"10.1080/19382014.2025.2610590","url":null,"abstract":"<p><strong>Objective: </strong>Mitochondria are central to energy production and cellular homeostasis. Beyond importing diverse RNAs, they also encode hundreds of their own non-coding RNAs, contributing to a complex and dynamic RNA landscape. Early-life nutritional insults, such as fetal and postnatal protein deficiency, can impair mitochondrial function and increase the long-term diabetes risk. However, the mitochondrial non-coding transcriptome of pancreatic islets, particularly its responsiveness to nutritional cues, remains largely unexplored.</p><p><strong>Methods: </strong>We performed RNA sequencing to profile small non-coding RNAs in mitochondrial fractions of islet cells from offspring of rats exposed to low-protein (LP) or control diets during gestation and lactation and employed mRNA-miRNA network analysis to explore the potential regulatory roles of differentially expressed mitomiRs in LP-exposed pups.</p><p><strong>Results: </strong>Protein deficiency during gestation and lactation led to a profound remodeling of the small non-coding RNA landscape in whole islets, with microRNAs and piRNAs showing the most pronounced changes. In mitochondrial fractions, LP exposure resulted in a striking shift in microRNA composition, with 33 mitomiRs detected in control islets versus 23 in LP-exposed rats, and only 5 shared between groups. Notably, ten mitomiRs were selectively depleted from the cytosol and enriched in mitochondria of LP-exposed islets. Amongst these, miR-10a-5p and miR-126a-5p, are predicted to target genes involved in mitochondrial metabolism and structural organization.</p><p><strong>Conclusion: </strong>Early-life protein restriction triggers a highly selective reorganization of the mitomiR landscape in pancreatic islets. The identified mitomiRs may serve as regulators of mitochondrial function and intracellular signaling, potentially influencing <i>β</i>-cell metabolic coupling and contributing to diabetes susceptibility.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"18 1","pages":"2610590"},"PeriodicalIF":1.7,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12758298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A geometry-informed continuous 3D IEQ framework enables more accurate dose estimation in stem cell-derived islet transplantation.","authors":"Yu Lu, Jinhui Fang, Zhongyi Jia, Pei Yang, Songtao Bi, Qianyun Liu, Zhe Yu, Jingyi Yin, Limin Chen, Rúben A Ricardo, Anup K Singh, Tongri Liu","doi":"10.1080/19382014.2026.2671454","DOIUrl":"10.1080/19382014.2026.2671454","url":null,"abstract":"<p><p>Accurate quantification of islet mass is critical for the preclinical evaluation and therapeutic application of stem cell-derived pancreatic islet organoids. Traditional methods, including Ricordi's islet equivalent (IEQ) approach and its equivalent circle diameter adaptations, often overestimate islet volume due to reliance on maximal diameters and discrete size bins. To address these limitations, we developed an automated image segmentation and three-dimensional modeling framework to quantify individual islet clusters from brightfield images. Clusters were fitted with ellipses and modeled as ellipsoids using rotation about either the minor or major axis, allowing IEQs to be calculated continuously relative to a reference 150 μm spherical islet. Major-axis (prolate) rotation provided the most conservative and physically plausible volume estimates, whereas minor-axis (oblate) rotation and diameter-based approaches systematically overestimated IEQs. Functional assessment with glucose-stimulated insulin secretion assays across multiple size categories demonstrated consistent insulin output for clusters below 250 μm, supporting the reproducibility of our 3D differentiation system. In vivo, streptozotocin-induced diabetic mice transplanted with islet doses based on major-axis modeling exhibited faster and more stable restoration of glycemia compared with groups receiving doses derived from overestimated approaches. These findings establish that major-axis ellipsoid modeling offers a mathematically consistent, conservative, and biologically relevant method for estimating IEQs, providing a practical framework to guide dosing in preclinical studies and supporting the translational development of stem cell-derived islet therapies.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"18 1","pages":"2671454"},"PeriodicalIF":1.4,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13166181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IFNα and bleomycin-induced DNA damage activate distinct stress responses in human islets and induced pluripotent stem cell-derived islet cells.","authors":"Roozbeh Akbari Motlagh, Nayara Rampazzo Morelli, Nicole Alcasid, Peter J Thompson","doi":"10.1080/19382014.2026.2692859","DOIUrl":"10.1080/19382014.2026.2692859","url":null,"abstract":"<p><p>Pancreatic β-cells undergo different stress responses during the development of type 1 diabetes (T1D), such as the type I interferon (IFN) response and senescence. Although the IFN response leads to endoplasmic reticulum (ER) stress and has been linked to senescence in other cell types, the extent to which senescence and the type I IFN response are related pathways in human β-cells are unclear. To address this question, we compared the transcriptional and protein secretory responses of human donor islets and induced pluripotent stem cell-derived islet cells (SC-islet cells) to IFNα and chemically-induced DNA damage using bleomycin. While IFNα induced a classical IFN response involving HLA Class I genes, ER stress genes, and reversible chemokine secretion, it did not lead to stable induction of senescence-related genes or a senescence-associated secretory phenotype (SASP) in human islets. Similarly, in SC-islet cell models derived from two donors with different HLA haplotypes, IFNα treatment led to the upregulation of IFN genes and HLA Class I genes without an effect on senescence genes or SASP. Conversely, bleomycin-induced DNA damage in SC-islet cells led to signatures of senescence without an effect on IFN genes, ER stress genes, or HLA Class I. Taken together, these data suggest that IFNα exposure and DNA damage elicit distinct stress responses in human donor islets and SC-islet cells. These findings have implications for our understanding of heterogeneity in β-cell stress in T1D.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"18 1","pages":"2692859"},"PeriodicalIF":1.4,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13360638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148421275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is the intraportal or renal subcapsular space a preferable site for islet allo- and xeno-transplantation? A brief historical review.","authors":"Sara De Taeye, Rita Bottino, David K C Cooper","doi":"10.1080/19382014.2026.2658317","DOIUrl":"10.1080/19382014.2026.2658317","url":null,"abstract":"<p><p>Diabetes mellitus and end-stage renal disease (ESRD) are major causes of morbidity and mortality worldwide.Pancreatic islet transplantation offers potential insulin independence. Different sites and their suitability for islet transplantation have been investigated, including renal subcapsular and intraportal sites, among others. Various limitations and complications have been reported, such as the number of donor islet species, islet isolation, and site of transplantation. Combining islets and kidney transplantation in diabetic patients suffering from ESRD has several advantages.This review compares the experimental experience of the renal subcapsular and intraportal sites for islet allo- and xeno-transplantation. The subcapsular site appears preferable in rodent models. The intraportal site has been more successful in large animals. Combined islet-kidneys have been suggested as a treatment targeting both ESRD and type 1 diabetes. With our increasing ability to genetically-engineer pigs, and the availability of novel immunosuppressive agents, xenotransplantation is an emerging therapeutic option.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"18 1","pages":"2658317"},"PeriodicalIF":1.4,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Annexin A1 exacerbates islet stellate cell activation by regulating triglyceride catabolism via the PPARα/ACOX1/CYP4a pathway.","authors":"Qing Li, Yan Zhang, Tianpei Yu, Li Shi, Qinqin Qiu, Ben Wang, Yiquan Sang, Rui Li, Qian Lv, Jie Wang, Xuekui Liu, Houfa Geng, Peter M Jones, Jun Liang, Wei Xu","doi":"10.1080/19382014.2026.2633793","DOIUrl":"10.1080/19382014.2026.2633793","url":null,"abstract":"<p><strong>Background: </strong>Activation of islet stellate cells (ISCs) contributes to islet fibrosis and diabetes progression through excessive extracellular matrix secretion and lipid loss. Annexin A1 (ANXA1) has been reported to modulate lipid metabolism in other tissues, but its role in ISCs remains unclear.</p><p><strong>Methods: </strong>ISCs were isolated from 9-and 28-week-old db/m and db/db mice. Lipid content analysis, qRT‒PCR, and Western blotting were used to assess lipid metabolism-related molecules. ANXA1 expression was analyzed by immunohistochemistry and Western blotting. Recombinant ANXA1 was co-cultured with db/db ISCs to evaluate lipid synthesis and lipolysis. The interaction between ANXA1 and peroxisome proliferator-activated receptor alpha (PPARα) was examined by immunoprecipitation.</p><p><strong>Results: </strong>Activation of ISCs markedly reduced intracellular triglycerides, with decreased Diacylglycerol Acyltransferase 1/2 (DGAT1/2) and increased adipose triglyceride lipase (ATGL) and hormone-sensitive triglyceride lipase (HSL) expression. ANXA1 was detected in islets, MIN6 cells, and their culture supernatants. Recombinant ANXA1 treatment lowered triglyceride levels and upregulated PPARα and its downstream genes, acyl-CoA oxidase 1 (ACOX1) and cytochrome P450 4 A (CYP4A); these effects were enhanced by a PPARα agonist but reversed by inhibition. Immunofluorescence and coimmunoprecipitation confirmed that PPARα acts as a key mediator of ANXA1-regulated triglyceride metabolism in ISCs.</p><p><strong>Conclusion: </strong>ANXA1 promotes ISCs activation by enhancing triglyceride catabolism through the PPARα signaling pathway, suggesting a novel therapeutic target for islet fibrosis.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"18 1","pages":"2633793"},"PeriodicalIF":1.4,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12928626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147270957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human and mouse regenerative macrophages enhance beta cell survival, function, and proliferation.","authors":"Mahdis Monajemi, Alexandra S Craciun, Qing Huang, Lei Dai, Majid Mojibian, Sarah Q Crome, C Bruce Verchere, Megan K Levings","doi":"10.1080/19382014.2026.2659457","DOIUrl":"10.1080/19382014.2026.2659457","url":null,"abstract":"<p><strong>Aims: </strong>Type 1 diabetes is caused by immune-mediated destruction of beta cells. Interestingly, individuals with long-standing type 1 diabetes have residual beta cells, suggesting regenerative mechanisms may help beta cell survival. Islet-resident macrophages have an important role in diabetes, and can adopt a tissue-regenerating phenotype that may support beta cells. However, the roles of macrophages in beta cell survival, function, and proliferation remain poorly defined. This study aimed to elucidate how macrophage subtypes influence beta cell survival, function, and proliferation.</p><p><strong>Methods: </strong>Mouse and human islets were isolated from the pancreas and co-cultured <i>in vitro</i> with macrophages. To investigate whether macrophages enhance beta cell survival and function, apoptosis was measured using flow cytometry, and insulin secretion was assessed via glucose-stimulated insulin secretion assays. We also examined whether macrophages increased beta cell proliferation in the presence of harmine, a DYRK1A inhibitor. Finally, we evaluated the effect of islet co-culture on macrophage phenotype by flow cytometry and cytokine secretion analysis.</p><p><strong>Results: </strong>We found that regenerative, but not pro-inflammatory, macrophages enhanced beta cell survival and function through mechanisms that did not require direct cell contact. Direct contact between macrophages and islets promoted a macrophage regenerative phenotype characterized by increased CD206 expression and secretion of anti-inflammatory factors. Additionally, regenerative macrophages promoted beta cell proliferation in the presence of harmine.</p><p><strong>Conclusions: </strong>Our findings demonstrate that regenerative macrophages support pancreatic beta cell survival, function, and proliferation. Harnessing the regenerative properties of macrophages could offer a novel strategy to promote beta cell survival and function.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"18 1","pages":"2659457"},"PeriodicalIF":1.4,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13154999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147815367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Importance of antibody validation in detecting cell cycle regulatory protein p16 ^<b>INK4A</b> by immunohistochemistry on pancreas tissue.","authors":"Jasmine Pipella, Peter J Thompson","doi":"10.1080/19382014.2026.2706228","DOIUrl":"10.1080/19382014.2026.2706228","url":null,"abstract":"<p><strong>Aims/objective: </strong>p16^INK4A is a cyclin-dependent kinase inhibitor that plays important roles in pancreatic islet beta-cell maturation, function, and senescence. As staining pattern consistency and reproducibility have been challenging in the field, our objective was to validate a monoclonal antibody for the detection of p16^INK4A in mouse and human fixed pancreas sections.</p><p><strong>Methods: </strong>Four commercial monoclonal antibodies reported to react against mouse p16^INK4A were tested by fluorescent immunohistochemistry on positive and negative control formalin-fixed paraffin-embedded pancreas sections from two different mouse strains. Lot-to-lot consistency was also evaluated. Fixed human donor pancreas sections were evaluated for reactivity with the monoclonal p16^INK4A antibody that performed best on mouse tissues.</p><p><strong>Results: </strong>One commercial monoclonal antibody robustly detected a nuclear antigen in both mouse and human pancreas sections, consistent with the previously reported p16^INK4A staining pattern, and its role as a cyclin-dependent kinase inhibitor in beta cells. This antibody also showed lot-to-lot consistency in staining pattern.</p><p><strong>Conclusion: </strong>Our findings highlight the importance of antibody validation for p16^INK4A detection in mouse and human pancreas sections and suggest caution in using untested commercially available antibodies to this protein for immunohistochemistry of the pancreas.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"18 1","pages":"2706228"},"PeriodicalIF":1.4,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of HNF4α knockout in beta cells is age and sex dependent.","authors":"Catharina B P Villaca, Viviane R Oliveira, Gustavo J Santos, Fernanda Ortis","doi":"10.1080/19382014.2025.2552549","DOIUrl":"10.1080/19382014.2025.2552549","url":null,"abstract":"<p><p>HNF4α is important for beta cells' ability to adequately secrete insulin in response to glucose concentration and endoplasmic reticulum (ER) homeostasis. In humans, HNF4α mutations are responsible for Diabetes <i>mellitus</i> subtype MODY1, which has an age-determining onset. Additionally, in other forms of DM, there is evidence that sex can influence beta cell dysfunction, with possible involvement of ER stress pathways. Thus, we assessed the influence of sex and age on beta-cell dysfunction induced by HNF4α absence. We used an animal model with specific beta cells KO of HNF4α, induced after birth (Ins. CRE HNF4α^loxP/loxP). Glucose intolerance is observed after 10 d of KO induction, at 50 d of age, with KO males (MKO) displaying more severe glucose intolerance than KO females (FKO). The percentage of insulin-positive cells in KO mice islets is lower compared to Control at all ages evaluated, with MKO mice showing a more pronounced decline at later ages compared to FKO. Both KO groups exhibited reduced beta cell mass and increased <i>α</i>-cell mass, which was more pronounced in MKO. ER stress was induced in both KO groups; however, ER stress-mediated apoptosis was observed only in MKO. FKO mice show evidence of beta cell differentiated state loss. In summary, beta cell loss in HNF4α-KO is influenced by sex and age, involves induction of ER stress, and is more severe in males, where ER stress-induced beta cell death is observed. Partial protection observed in females seems to involve dedifferentiation of beta cells.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"17 1","pages":"2552549"},"PeriodicalIF":1.7,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction.","authors":"","doi":"10.1080/19382014.2025.2557668","DOIUrl":"10.1080/19382014.2025.2557668","url":null,"abstract":"","PeriodicalId":14671,"journal":{"name":"Islets","volume":"17 1","pages":"2557668"},"PeriodicalIF":1.7,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12427519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of free fatty acid-free bovine serum albumin and palmitate on pancreatic β-cell function.","authors":"Katherine Sentjens, Renjitha Pillai, Jamie W Joseph","doi":"10.1080/19382014.2025.2479911","DOIUrl":"10.1080/19382014.2025.2479911","url":null,"abstract":"<p><p>Pancreatic β-cells release insulin in response to fluctuations in plasma glucose, amino acids, and free fatty acids (FFA). Clonal cell lines and isolated islets serve as essential early models for studying the impact of nutrients and evaluating potential therapies to address β-cell dysfunction. Acute and chronic changes in FFA levels have been shown to have positive and negative effects on β-cell function both <i>in vivo</i> and <i>in vitro</i>. A key problem in comparing islet lipid studies from different laboratories is that a wide variety of methods are used to isolate, culture, and assess islet function. The current study compares bovine serum albumin (BSA) types and lipid preparation methods in clonal 832/13 cells and human islets. Changing the percentage and culture conditions when using FFA-free BSA can negatively affect β-cell function compared to regular BSA. Preparing palmitate with FFA-free BSA can rescue insulin secretion compared to treating cells alone with FFA-free BSA. Different methods of preparing palmitate can have unique effects on insulin secretion. Overall, interpreting the effects of lipids on β-cell function is complicated by a number of variables that need to be controlled for in islet experiments.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"17 1","pages":"2479911"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11917175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}