{"data":{"id":"cmvfku7060000kj08384m2n8z","contentHash":"319f8f23bf7a5935924f1f878124b68c4fdc103a580fa3bb16bb740ead991196","data":{"known":{"query":"(EXT_ID:39326417 OR EXT_ID:41765034 OR EXT_ID:40757665) AND SRC:MED","records":[{"id":"41765034","doi":"10.1016/s2213-8587(25)00423-1","title":"Autologous and allogeneic stem cell-derived islet therapy in three recipients with type 1 diabetes and complete loss of endogenous pancreatic β-cell function pretransplant.","source":"MED","abstract":"","sourceUrl":"https://europepmc.org/article/MED/41765034","publicationTypes":["Letter"],"commentsCorrections":null,"firstPublicationDate":"2026-02-26"},{"id":"40757665","doi":"10.1056/nejmoa2503822","title":"Survival of Transplanted Allogeneic Beta Cells with No Immunosuppression.","source":"MED","abstract":"The need to suppress a patient's immune system after the transplantation of allogeneic cells is associated with wide-ranging side effects. We report the outcomes of transplantation of genetically modified allogeneic donor islet cells into a man with long-standing type 1 diabetes. We used clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 12b (Cas12b) editing and lentiviral transduction to genetically edit the cells to avoid rejection; the cells were then transplanted into the participant's forearm muscle. He did not receive any immunosuppressive drugs and, at 12 weeks after transplantation, showed no immune response against the gene-edited cells. C-peptide measurements showed stable and glucose-responsive insulin secretion. A total of four adverse events occurred, none of which were serious or related to the study drug. (Funded by the Leona M. and Harry B. Helmsley Charitable Trust; EudraCT number, 2023-507988-19-00; ClinicalTrials.gov number, NCT06239636.).","sourceUrl":"https://europepmc.org/article/MED/40757665","publicationTypes":["Journal Article","Case Reports"],"commentsCorrections":{"commentCorrection":[{"id":"41406457","type":"Comment in","source":"MED","orderIn":1,"reference":"N Engl J Med. 2025 Dec 18;393(24):2486. doi: 10.1056/NEJMc2516172."},{"id":"41406458","type":"Comment in","source":"MED","orderIn":2,"reference":"N Engl J Med. 2025 Dec 18;393(24):2486-2487. doi: 10.1056/NEJMc2516172."}]},"firstPublicationDate":"2025-08-04"},{"id":"39326417","doi":"10.1016/j.cell.2024.09.004","title":"Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient.","source":"MED","abstract":"We report the 1-year results from one patient as the preliminary analysis of a first-in-human phase I clinical trial (ChiCTR2300072200) assessing the feasibility of autologous transplantation of chemically induced pluripotent stem-cell-derived islets (CiPSC islets) beneath the abdominal anterior rectus sheath for type 1 diabetes treatment. The patient achieved sustained insulin independence starting 75 days post-transplantation. The patient's time-in-target glycemic range increased from a baseline value of 43.18% to 96.21% by month 4 post-transplantation, accompanied by a decrease in glycated hemoglobin, an indicator of long-term systemic glucose levels at a non-diabetic level. Thereafter, the patient presented a state of stable glycemic control, with time-in-target glycemic range at >98% and glycated hemoglobin at around 5%. At 1 year, the clinical data met all study endpoints with no indication of transplant-related abnormalities. Promising results from this patient suggest that further clinical studies assessing CiPSC-islet transplantation in type 1 diabetes are warranted.","sourceUrl":"https://europepmc.org/article/MED/39326417","publicationTypes":["Clinical Trial, Phase I","Journal Article"],"commentsCorrections":{"commentCorrection":[{"id":"39642862","type":"Comment in","source":"MED","orderIn":1,"reference":"Cell Stem Cell. 2024 Dec 5;31(12):1727-1729. doi: 10.1016/j.stem.2024.11.011."}]},"firstPublicationDate":"2024-09-25"}],"hitCount":3},"policy":"Automatically retrieved publication metadata and abstracts, not automatic clinical adjudication. Correction/retraction metadata is incomplete; compare primary sources and keep conflicts. Existing reviewed narrative is not silently rewritten. Agent Council ratifies conclusions.","version":"patient-reference-1","discovery":{"query":"(TITLE_ABS:\"type 1 diabetes\") AND (TITLE_ABS:islet OR TITLE_ABS:\"beta cell\") AND (TITLE_ABS:transplantation OR TITLE_ABS:immunosuppression OR TITLE_ABS:hypoimmune) SORT_DATE:y","records":[{"id":"42850666","doi":"10.1002/advs.78154","title":"Immune Biomarkers of Islet Transplant Rejection Revealed by Synthetic Immunological Niche.","source":"MED","abstract":"Islet transplantation can restore glycemic control in type 1 diabetes, yet heterogeneity of immune responses and transplant outcomes necessitates improved graft monitoring. Since transplanted islets are diffusely engrafted within the liver and inaccessible to biopsy, clinical monitoring relies on blood glucose and C-peptide, which change only after substantial graft injury. Here, we developed a synthetic immunological niche (IN) that captures graft-associated immune responses through serial subcutaneous biopsy. We evaluated the IN across murine syngeneic, allogeneic, and autoimmune islet transplant models, including CD40/CD154 blockade with anti-CD40L. The IN identified immune populations and transcriptomic signatures reflective of the graft and distinguished syngeneic from rejecting allografts. In anti-CD40L-treated allografts, the IN revealed innate immune programs characterized by macrophage- and dendritic cell-associated signatures linked to acceptance versus rejection, whereas untreated allografts showed stronger adaptive immune signatures. Longitudinal IN profiling detected inflammatory activation in accepted allografts, indicating persistent subclinical risk. Finally, in autoimmune allografts treated with anti-CD40L plus rapamycin, IN identified a 13-gene signature that separated early from late rejection and distinguished autoimmune- from alloimmune-associated rejection programs. These findings establish the IN as a platform for identification of early biomarkers of islet graft rejection before overt dysfunction, addressing an unmet need in islet transplant monitoring.","sourceUrl":"https://europepmc.org/article/MED/42850666","publicationTypes":["research-article","Journal Article"],"commentsCorrections":{"commentCorrection":[{"id":"42239111","type":"Update of","source":"MED","orderIn":1,"reference":"bioRxiv. 2026 May 18:2026.05.14.725252. doi: 10.64898/2026.05.14.725252."},{"id":"PPR1209331","note":"Link created based on a title-first author match","type":"Preprint in","source":"PPR","orderIn":10002}]},"firstPublicationDate":"2026-10-08"},{"id":"PPR1338256","doi":"10.64898/2026.10.01.756003","title":"Islet size and spatial organization govern endocrine cell composition throughout the human pancreas","source":"PPR","abstract":"Stem cell-derived (SC) islets hold promise as a transformative therapy for type 1 diabetes (T1D). To enhance graft uniformity, SC-islet organoids are often dissociated and reaggregated into standardized sizes. However, how endocrine cell composition varies with islet size in native human islets remains largely unknown. Defining this relationship is essential for establishing physiological benchmarks for islet engineering for transplantation. In this study, we examined the relationships among islet size, endocrine cell composition, and spatial distribution throughout whole pancreata from 10 age-matched, non-diabetic male subjects. Insulin-, glucagon-, and somatostatin-positive endocrine cells were identified as single-, double-, and triple-hormone populations ranging from non-islet single endocrine cells and small clusters (niSSCs) to large islets. Approximately 80% of the total endocrine area was contained in islets positive for all three hormones. Islet size strongly correlated with endocrine composition. Specifically, larger islets had increased alpha-cell fractions and reduced beta-cell fractions, while delta-cell fractions were consistent across sizes. Spatial analysis revealed that niSSCs, mono-, and tri-hormone islets frequently exhibit a clustered distribution. Additionally, tri-hormone islets were positioned near the core of the pancreas, whereas mono-somatostatin islets were often localized in the periphery. These findings were consistent across all three pancreatic regions (head, body and tail).","sourceUrl":"https://europepmc.org/article/PPR/PPR1338256","publicationTypes":["Preprint"],"commentsCorrections":null,"firstPublicationDate":"2026-10-08"},{"id":"42876362","doi":"10.1111/imr.70182","title":"Oxidative Stress, Post-Translational Modifications, and Type 1 Diabetes Pathogenesis.","source":"MED","abstract":"Type 1 diabetes (T1D) is an organ-specific autoimmune disease that destroys insulin-producing beta-cells. Insulin is a vital hormone for regulating glycemia that often undergoes post-translational modifications during processing from pre-proinsulin to biologically active insulin. While necessary for proper glucose homeostasis, insulin is also an autoantigen recognized by autoreactive T cells in T1D. Cellular stress pathways including endoplasmic reticulum stress and oxidative stress mediated by an increase in reactive oxygen species (ROS) synthesis and/or a concomitant decrease in antioxidant function can further drive post-translational modifications of various autoantigens in T1D including insulin. Innate immune-derived ROS generation is an essential frontline defense against microbial infections, but ROS can also function as signaling intermediates to properly stimulate T cell responses. Oxidative stress-induced post-translational modifications are thought to trigger autoreactive T cells in T1D by generating novel neoepitopes, eliciting epitope spreading, or enhancing autoantigen interactions with antigen-presenting cells. With the current technology, detecting post-translationally modified proteins is challenging. In this review, we will explore the role of ROS and other post-translational modifications involved in T1D. We will also discuss islet transplantation strategies being used for patients with T1D including novel cell sources for beta-cell replacement and management of oxidative stress after transplantation.","sourceUrl":"https://europepmc.org/article/MED/42876362","publicationTypes":["Review","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-10-01"},{"id":"PPR1322417","doi":"10.64898/2026.09.12.751148","title":"Bridging scale-up to transplantation: pluripotent stem cell-derived pancreatic islet encapsulation in emulsion-generated high concentration alginate beads","source":"PPR","abstract":"Pluripotent stem cell-derived pancreatic islet-like cell clusters (SC-islets) have emerged as potential cellular therapy for type 1 diabetes. While SC-islets can theoretically be produced in bioreactors to meet transplantation needs of many recipients per batch, biomanufacturing and translational challenges remain. SC-islet can be cultured in suspension using stirred tank or vertical wheel bioreactors, but these can impart hydrodynamic damage and lead to cellular agglomeration, particularly upon scale-up. We previously described a robust emulsion-based process to encapsulate murine pancreatic beta cells in high-concentration alginate beads which improved graft survival in allogeneic recipients. Here, we present a full pipeline for scalable microencapsulated SC-islet biomanufacturing with extended  in vitro bioreactor culture leading into transplantation. We hypothesized that encapsulation would prevent cellular agglomeration, reduce mechanical stress, and preserve differentiation potential during scale-up. Encapsulation of Stage 6 SC-islets prevented cellular agglomeration during extended suspension culture (25 days) and increased cell recovery (91 ± 3%) compared with non-encapsulated aggregates (60 ± 10%). No significant differences in glucose-stimulated insulin secretion were observed with vs without microencapsulation. Stage 7 SC-islets matured in the bioreactor were transplanted either as encapsulated islets via the intraperitoneal route or as free SC-islets under the kidney capsule, where they displayed glucose-responsive human C-peptide secretion and remained functional  in vivo for up to 98 days. Overall, this work establishes a scalable, robust, transplantation-ready encapsulation platform that supports SC-islet maturation and delivery, providing a generalizable strategy for scaling and transplanting encapsulated organoid systems.","sourceUrl":"https://europepmc.org/article/PPR/PPR1322417","publicationTypes":["Preprint"],"commentsCorrections":null,"firstPublicationDate":"2026-09-18"},{"id":"42750143","doi":"10.1111/aor.70245","title":"Engineering Immune-Protective Stem Cell-Derived β-Cell Grafts for Type 1 Diabetes: Encapsulation Technologies and the Emerging Graft Ecosystem.","source":"MED","abstract":"<h4>Background</h4>Stem cell-derived β-cell replacement has emerged as a promising strategy for the treatment of type 1 diabetes (T1D), potentially addressing the limitations of exogenous insulin therapy and donor-dependent islet transplantation. However, despite substantial progress in stem cell differentiation and transplantation technologies, long-term graft survival remains constrained by immune rejection, recurrent autoimmunity, fibrosis, hypoxia, and inadequate vascularization. Encapsulation technologies have therefore become central to the development of clinically viable bioartificial pancreas systems.<h4>Methods</h4>This review examines advances in stem cell-derived β-cell replacement, with particular emphasis on encapsulation technologies and their translational challenges. Major stem cell sources, including embryonic stem cells and induced pluripotent stem cells, contemporary differentiation strategies, and clinical progress were evaluated. Microencapsulation, macroencapsulation, and conformal coating approaches were critically considered with respect to immunoprotection, mass transport, retrievability, and long-term graft functionality. Biological barriers and emerging engineering strategies were further integrated within a unified mechanistic framework.<h4>Results</h4>Current evidence indicates that successful long-term β-cell replacement is limited not only by immune-mediated injury but also by foreign body responses, pericapsular fibrosis, hypoxia, inadequate vascular integration, and compromised mass transport. Emerging approaches, including oxygen-generating biomaterials, immunomodulatory encapsulation systems, vascularization-promoting platforms, smart responsive biomaterials, and gene-edited hypoimmune β-cells, are being developed to overcome these barriers. Collectively, these advances indicate that durable graft function requires coordinated regulation of immunity, oxygenation, vascularization, and tissue homeostasis rather than the generation of functional insulin-producing cells alone.<h4>Conclusions</h4>Durable β-cell replacement for T1D will likely require engineering a supportive graft ecosystem rather than focusing exclusively on cell replacement. The field is consequently transitioning from cell replacement engineering toward graft ecosystem engineering, in which stem-cell engineering, biomaterials science, immune modulation, vascularization strategies, and biosensing technologies are integrated to create clinically scalable and durable therapeutic platforms.","sourceUrl":"https://europepmc.org/article/MED/42750143","publicationTypes":["Review","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-09-16"},{"id":"42690930","doi":"10.1016/j.celrep.2026.117941","title":"Engineering the insulin signal peptide to protect human pancreatic beta cells from autoimmune destruction.","source":"MED","abstract":"Autoreactive T cells that destroy beta cells in type 1 diabetes are largely targeting insulin signal peptide fragments. HLA knockout beta-cells have been proposed to create hypo-immune cells, but this strategy poses significant tumorigenic risks. Alternatively, we hypothesized that insulin signal peptide modification would give rise to beta cells evading autoimmune recognition while maintaining insulin functionality. We developed human beta-cell lines lacking endogenous insulin and complemented them with insulin-carrying signal peptides from different hormones including chromogranin-A. We evaluated insulin synthesis, processing, secretion, activity, and immune evasion. Chromogranin-A signal peptide substitution directed insulin expression, maturation, and secretion, maintaining physiological proinsulin/insulin ratios. Secreted insulin remained functional. Crucially, beta cells expressing insulin with chromogranin-A signal peptide evaded recognition and killing by autoreactive T cells without inducing ER stress or compromising cellular identity. This approach may offer a targeted alternative to systemic immunosuppression to be used in stem-cell-derived therapies by engineering endogenous insulin signal peptide.","sourceUrl":"https://europepmc.org/article/MED/42690930","publicationTypes":["Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-09-03"},{"id":"42626948","doi":"10.1080/14712598.2026.2721412","title":"Gene-edited hypoimmune islets as a cure for type 1 diabetes: a review of the immunological challenges.","source":"MED","abstract":"<h4>Introduction</h4>Islet transplantation has long been considered a potential long-term treatment for type 1 diabetes mellitus (T1DM); however, the need for systemic immunosuppression has limited its clinical utility due to associated toxicity. Gene-edited hypoimmune islets represent a promising immunosuppression-free alternative. Recent first-in-human data demonstrating short-term engraftment and C-peptide production without immunosuppression, with 12-week immune monitoring and extended 14-month follow-up, provide an important proof-of-concept. However, whether short-term immune evasion can translate into durable long-term graft survival remains unclear.<h4>Areas covered</h4>We critically evaluate current preclinical and clinical evidence from 2019 to 2026 for gene-edited hypoimmune islets, highlighting key immunological vulnerabilities that may emerge over time.<h4>Expert opinion</h4>The central question is no longer whether these islets can evade acute rejection, but whether they can sustain this evasion and efficacy long-term against the human immune system. Several theoretical mechanisms may contribute to delayed graft injury: indirect allorecognition (particularly non-HLA antibody formation), persistence of autoreactive immune memory, β-cell stress-induced neoantigen formation, and susceptibility to viral infection. Durable graft survival will likely require multimodal approaches combining gene-edited islets with adjunct immunomodulation (e.g. teplizumab, low-dose ATG, tegoprubart) and metabolic support. If these long-term challenges can be overcome, gene-edited hypoimmune islets could transform T1DM treatment paradigms.","sourceUrl":"https://europepmc.org/article/MED/42626948","publicationTypes":["Review","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-09-03"},{"id":"42789342","doi":"10.1002/cpz1.70467","title":"A Stepwise Method to Derive Functional Pancreatic Islet-like Clusters from Human Pluripotent Stem Cells.","source":"MED","abstract":"The most common treatment for people with people with type 1 diabetes (T1D) requires injections of exogenous insulin to regulate blood glucose homeostasis. A longer-term therapeutic solution for T1D has emerged whereby patients may regain insulin independence through transplantation of donated human pancreatic islets, which contain insulin-secreting beta (β)-cells. Donated islets, however, are in short supply. Much effort has been dedicated to using human pluripotent stem cell (hPSC)-derived islets (SC-islets) as an unlimited source of insulin-secreting β-cells. Here, we describe a robust and reproducible 40-day, seven-stage stepwise process for generating hPSC-derived SC-islets. Our differentiation protocol aims to mimic in vivo pancreas development using stage-specific signals to promote the generation of SC-islets. The initial maintenance and the first four stages are performed in two-dimensional monolayer culture; the subsequent three stages require three-dimensional culture in microwells to induce the formation of islet-like clusters. The SC-islets generated at the end of the procedure respond to glucose challenges, reliably express appropriate endocrine markers, contain intracellular insulin, and display an islet-like architecture. Most SC-islets also partially express maturity markers that are often challenging to activate in vitro. These protocols thus provide a scalable platform for generating SC-islets for disease modeling and cell replacement studies. © 2026 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Thawing, recovery, and passaging of cryopreserved hPSCs Support Protocol 1: Preparation of solutions and media for hPSC maintenance and expansion Support Protocol 2: Preparation of Matrigel-coated plates for passaging hSPCs Basic Protocol 2: Differentiation of hPSCs to SC-islets.","sourceUrl":"https://europepmc.org/article/MED/42789342","publicationTypes":["methods-article","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-09-01"},{"id":"42778262","doi":"10.1111/xen.70170","title":"Flow Cytometric Immune Profiling Enables Early Detection of Rejection in Islet Xenotransplantation.","source":"MED","abstract":"<h4>Background</h4>Islet xenotransplantation is a strategy for treatment of Type 1 Diabetes, but immune-mediated rejection limits graft survival. This study investigated a strategy with flow cytometry-based immune monitoring to evaluate immunosuppressive therapy and provide indicators of graft rejection.<h4>Methods</h4>Porcine neonatal islet cell clusters (NICC) from GTKO-hCD55-hCD59 transgenic pigs were transplanted into streptozotocin-induced diabetic baboons (n = 10). Recipients received anti-CD2 induction with anti-CD154, Belatacept, and full-dose (n = 7) or reduced/no dose Tacrolimus (n = 3). Leukocyte subsets and activation status were monitored using multiplex flow cytometry. Graft function was assessed by blood glucose measurements, porcine C-peptide ELISA, and histological analysis.<h4>Results</h4>Porcine C-peptide was detected in all recipients. Seven animals receiving full-dose Tacrolimus maintained NICC function for up to 675 days, whereas three experienced acute rejection within two months. Flow cytometry generated absolute leukocyte counts equivalent to standard full blood counts (Deming regression slope 0.91-1.03, p<0.001), while requiring less blood (50 µl vs ∼500 µl) and processing time (50±15 vs 150±30 min). Anti-CD2 treatment significantly reduced unoccupied surface CD2 on circulating T cells (mean 73.21%, range 55.26-91.16%, p<0.001). Long-term graft survival was associated with greater first-month T-cell suppression (36.47%, 13.35-50.75%) than acute rejection (176.28%, 171.26-181.31%). Following immunosuppression withdrawal, lymphocyte counts increased by 40%-142% in all recipients. Multiplex immunofluorescence of endpoint grafts from these IS-free animals revealed cell-mediated destruction with increased lymphocyte infiltration and activated cytotoxic CD8<sup>+</sup> T cells.<h4>Conclusion</h4>Multiplex flow cytometry provides a reliable method for immune monitoring in islet xenotransplantation and may help predict graft rejection.","sourceUrl":"https://europepmc.org/article/MED/42778262","publicationTypes":["research-article","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-09-01"},{"id":"42711287","doi":"10.1111/xen.70164","title":"Quantification of Islet Cell Cluster Size Heterogeneity in Early Postnatal Porcine Pancreas.","source":"MED","abstract":"Donor scarcity limits islet transplantation for type 1 diabetes. Early postnatal piglets are a potential xenogeneic source of endocrine tissue, yet their immature islet cell clusters (ICCs) remain insufficiently characterised with respect to size and maturation. Here, we quantified ICC size heterogeneity in pancreata from six 14-day-old piglets using insulin and glucagon immunofluorescence staining and large-area immunofluorescence imaging with automated whole-section analysis. ICCs were classified as small (1-2 endocrine cells), intermediate (3-5 endocrine cells), or large (≥6 endocrine cells). Well-developed ICCs reaching ∼100 µm in diameter were consistently identified in all animals and exhibited an intermingled β- and α-cell cytoarchitecture similar to that of adult pig and human islets. The densities of small, intermediate, and large clusters were largely comparable among littermates and across piglets, suggesting a consistent distribution of ICC size classes at this postnatal age. Quantitative composition analysis revealed a strong predominance of insulin-positive area. In small and intermediate ICCs, we observed mean β/α cell ratios of 3.7 ± 0.4 and 3.8 ± 0.4, respectively. In large ICCs, the proportion of glucagon staining was significantly higher, decreasing the β/α cell ratio to 2.2 ± 0.3. Together, these data point to a reproducible distribution of ICC sizes in 14-day-old piglet pancreata, including a population of morphologically well-developed, ∼100 µm-sized clusters. These findings from native pancreatic tissue provide a morphological basis for further evaluating 14-day-old piglets as a potential donor source for xenogeneic islet transplantation.","sourceUrl":"https://europepmc.org/article/MED/42711287","publicationTypes":["research-article","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-09-01"},{"id":"42571658","doi":"10.1002/dmrr.70215","title":"Advancing Type 1 Diabetes Treatment: 3 PM-Oriented Innovations in Islet Transplantation and Biomaterial Engineering.","source":"MED","abstract":"Type 1 Diabetes (T1D) is an autoimmune disorder marked by the immune-mediated destruction of pancreatic β-cells, resulting in insulin deficiency and dysregulated glucose control. Current therapies-such as insulin replacement and artificial pancreas systems-manage symptoms but fail to restore endogenous β-cell function or halt disease progression. Transplantation strategies, including islet allo- and xenotransplantation, offer potential cures but remain limited by immune rejection, donor scarcity, and the adverse effects of systemic immunosuppression. Within the framework of predictive, preventive, and personalised medicine (3 PM), T1D management requires a paradigm shift towards early detection, targeted prevention, and individualised therapy. Predictive biomarkers and molecular phenotyping can identify high-risk individuals and forecast graft outcomes, while preventive strategies-such as localised immunomodulation, bioenergetic support, and control of systemic inflammation-improve tolerance and graft longevity. Personalised interventions, including patient-specific biomaterials, immunoprotective encapsulation, and regulatory T cell-based or stem-cell-derived β-cell replacement, address immune and metabolic heterogeneity. Recent progress in biomaterials, encapsulation, and 3D bioprinting enables the practical implementation of this 3 PM approach by enhancing oxygenation, vascular integration, and specific scaffold design. Integration of AI-driven analytics, digital health monitoring, and multi-modal diagnostics further supports predictive control of transplant outcomes. This review highlights advances in islet transplantation and regenerative biomaterial engineering as key enablers of the transition from reactive treatment to 3 PM-guided, patient-tailored therapy for T1D.","sourceUrl":"https://europepmc.org/article/MED/42571658","publicationTypes":["review-article","Review","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-09-01"},{"id":"42439827","doi":"10.2337/db26-0013","title":"Applications of Stem Cell-Derived Islets and Emerging Experimental Platforms to Understand Diabetes.","source":"MED","abstract":"Type 1 diabetes (T1D) impacts more than 9 million individuals globally. Despite a century since the isolation and clinical introduction of insulin, exogenous insulin injections remain the primary form of treatment for T1D. While continuous glucose monitoring systems and optimized insulin delivery reduce life-threatening hypoglycemic events, they do not provide a permanent cure. Transplantation of pancreatic islets offers a potential long-term solution. Recent advances in stem cell-derived islets (SC-islets) have shown remarkable promise in both clinical and research settings. This article highlights recent clinical reports in the use of SC-islets to restore islet function and their versatility as a platform for disease modeling and drug screening while emphasizing current strategies aimed at overcoming their limitations and enhancing their therapeutic potential. We also discuss exciting emerging approaches that expand investigations beyond pancreatic endocrine cells to encompass nonendocrine cell types in the pancreas, offering a unique bird's-eye view into pancreatic biology and insights into cellular cross talk in health and disease. Our aim is for this article to serve as a resource for up-to-date advances in SC-islet research and to highlight novel platforms for studying diabetes pathogenesis in unprecedented ways, accelerating progress toward a permanent cure.<h4>Article highlights</h4>Stem cell-derived islets provide a renewable source of insulin-producing cells for studying diabetes and developing regenerative therapies. Stem cell-derived islets are still functionally immature in comparison with primary human islets, underscoring the need for deeper insights into β-cell biology to improve their fidelity. Nonetheless, they serve as a powerful platform for diabetes disease modeling. Emerging technological advances, including spatial multiomics and multicellular organoid development, are revealing key roles for non-β-cell and nonislet cell types in pancreatic diseases. Integrating these emerging tools is critical for broadening our understanding of diabetes pathophysiology and may enable us to view the disease from previously unexplored perspectives.","sourceUrl":"https://europepmc.org/article/MED/42439827","publicationTypes":["review-article","Review","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-09-01"},{"id":"42411999","doi":"10.2337/dc26-0795","title":"Type 1 Diabetes Driven by Residual Recipient T Cells After Hematopoietic Cell Transplantation: A Case Report.","source":"MED","abstract":"<h4>Objective</h4>Posttransplant type 1 diabetes (T1D) is typically attributed to transferred donor autoimmunity. We investigated a distinct etiology in a patient who developed diabetes following haploidentical hematopoietic cell transplantation, assessing whether autoimmunity originated from donor or residual host cells.<h4>Research design and methods</h4>Leveraging HLA disparity between the haploidentical donor and recipient, we used HLA class II tetramers to enumerate islet-specific CD4+ T cells in peripheral blood restricted by shared versus recipient-only HLA alleles.<h4>Results</h4>Tetramer analysis revealed an expanded population of islet-specific T cells in the recipient. The donor showed no such expansion. Despite 99% donor T-cell chimerism, >80% of the islet-specific T cells were restricted by recipient-unique HLA alleles, suggesting they originated from the residual host fraction.<h4>Conclusions</h4>T1D in this patient was most likely driven by residual recipient-derived T cells. Their survival despite myeloablative conditioning and repeated immunotherapy underscores the remarkable durability of established islet autoimmunity.","sourceUrl":"https://europepmc.org/article/MED/42411999","publicationTypes":["research-article","Journal Article","Case Reports"],"commentsCorrections":null,"firstPublicationDate":"2026-09-01"},{"id":"42739778","doi":"10.3390/jcm15176774","title":"Clinical Evolution, Outcomes, and Emerging Preservation Technologies in Pancreas and Islet Transplantation.","source":"MED","abstract":"Historically regarded as competitive modalities, pancreas and islet transplantation are increasingly recognized as complementary approaches to beta-cell replacement therapy. While whole-organ pancreas transplantation remains the established gold standard, islet transplantation has transitioned into an effective clinical alternative for selected cohorts of patients suffering from type 1 diabetes. This review provides a comprehensive evaluation of the clinical evolution characterizing these therapeutic modalities, tracing the shift from static cold storage (SCS) toward innovative dynamic preservation technologies, and exploring potential markers for predicting clinical outcomes. A focus on immunosuppression in islet transplantation is provided, emphasizing precise, tolerance-inducing strategies and investigating costimulation blockade, regulatory T-cell (Treg)-based therapies, and biomaterial-enabled local immunoprotection, with the aim of facilitating long-term graft survival while mitigating the metabolic and renal toxicities secondary to chronic calcineurin inhibitor exposure. Current evidence related to the transition from conventional SCS to advanced perfusion platforms, namely hypothermic machine perfusion (HMP), oxygenated hypothermic perfusion (HOPE), normothermic ex vivo perfusion (NEVP), and normothermic regional perfusion (NRP) is examined: the literature suggests that dynamic pancreas preservation platforms may improve metabolic recovery and some islet isolation outcomes; however, evidence that HOPE specifically reduces ischemia-reperfusion injury and consistently increases islet yield in the pancreas remains limited. Although normothermic perfusion provides significant utility for real-time viability assessment and graft reconditioning, its widespread clinical implementation remains constrained by technical impediments, notably interstitial edema. Ultimately, preservation efficacy is conceptualized not merely as a discrete preservation option, but as a multidimensional construct integrating biological integrity, graft usability, and recipient clinical outcomes.","sourceUrl":"https://europepmc.org/article/MED/42739778","publicationTypes":["review-article","Review","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-08-31"},{"id":"42667390","doi":"10.1007/s00125-026-06843-x","title":"Metabolic and macrovascular outcomes following simultaneous pancreas-kidney transplantation and kidney transplantation alone in recipients with type 1 diabetes mellitus: a systematic review and meta-analysis.","source":"MED","abstract":"<h4>Aims/hypothesis</h4>Simultaneous pancreas-kidney transplantation (SPKTx) and kidney transplantation alone (KTx) are common treatment modalities for individuals with type 1 diabetes with end-stage kidney disease. This study compared metabolic and macrovascular disease outcomes between SPKTx and KTx in recipients with type 1 diabetes.<h4>Methods</h4>We conducted a systematic search of the Embase, MEDLINE and Scopus databases (last searched 23 February 2025). We included retrospective and case-control studies, owing to a lack of randomised controlled trials in English, with adult patients. We excluded studies reporting on a return to dialysis post transplant, islet-kidney transplantation or separate pancreas-kidney transplants. Bias and study quality were assessed via the Newcastle-Ottawa scale for cohort studies. Demographic and outcome data were synthesised as both categorical and continuous data, with pooled means and summary statistics computed where applicable. Meta-analysis was performed on post-transplant outcomes in studies evaluating total cholesterol (TC), triglyceride (TG) level, HDL, LDL, blood pressure, HbA<sub>1c</sub> and renal function. Macrovascular outcomes included the frequency of new or adverse events associated with coronary artery disease (CAD), cerebrovascular disease (CeVD) and peripheral vascular disease (PVD).<h4>Results</h4>A total of 15 studies (n=564 SPKTx, 419 KTx) were included. Meta-analysis demonstrated lower post-transplant TC (mean difference -0.41 mmol/l [95% CI -0.60, -0.22], p<0.01, I<sup>2</sup>=37%), TG level (mean difference -0.76 mmol/l [95% CI -1.02, -0.49], p<0.01, I<sup>2</sup>=86%), LDL (mean difference -0.28 mmol/l [95% CI -0.42, -0.14], p<0.01, I<sup>2</sup>=15%), HbA<sub>1c</sub> (mean difference -28.79 mmol/mol [95% CI -35.75, -21.82], p<0.01, I<sup>2</sup>=98%; mean difference -2.61% [95% CI -3.05, -2.16], p<0.01) and creatinine levels (mean difference -21.54 μmol/l [95% CI -39.23, -3.85], p=0.02, I<sup>2</sup>=90%) following SPKTx compared with KTx. Mean antihypertensive agent use per participant decreased post SPKTx (1.0 vs 2.5 pre transplant; p<0.01), but was not significantly different from post-KTx groups. HbA<sub>1c</sub> increased following KTx (69 mmol/mol [8.5%]) compared with pre KTx (53 mmol/mol [7.0%], p<0.01). Progression of CAD, CeVD and PVD occurred across both groups post transplant. PVD showed more than a twofold increase in amputations and revascularisations post transplant. No difference was observed in the post-transplant frequency of CAD, CeVD or PVD between SPKTx and KTx. Evidence from this study was limited by a lack of subgroup data for analysis, a lack of randomised studies and a paucity of reported lifestyle factors influencing outcomes.<h4>Conclusions/interpretation</h4>SPKTx demonstrates a superior metabolic profile post transplant to that in KTx in recipients with type 1 diabetes. However, this does not translate into differences in the risk of CAD or PVD post transplant, with PVD accounting for the greatest burden of macrovascular disease.<h4>Registration</h4>This protocol has been registered a priori on PROSPERO (CRD42024622408).","sourceUrl":"https://europepmc.org/article/MED/42667390","publicationTypes":["Meta-Analysis","Systematic Review","review-article","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-08-29"},{"id":"42666090","doi":"10.1111/dme.70456","title":"PPI and researcher perspectives of islet transplantation therapy for type 1 diabetes.","source":"MED","abstract":"<h4>Aims</h4>Islet transplantation offers the potential of a cure for type 1 diabetes (T1D), but the limited availability of human donor islets means that this therapy is currently only available to a small group of people with T1D who have intractable hypoglycaemia. The shortage of donor human islets has driven extensive research efforts to generate human islets from pluripotent stem cells (SC-islets), and current protocols are producing SC-islets which are showing promising results in early clinical trials. As part of our T1D Grand Challenge research programme, we set up a Patient and Public Involvement (PPI) Steering Group with a diverse range of members with lived experience of T1D to interact with us and provide advice. The aim of this study was to explore how perceptions of human islet transplantation differ between people with lived experience of T1D and diabetes researchers.<h4>Methods</h4>To determine how perceptions of human islet transplantation may differ between people with lived experience of T1D and researchers, two islet transplant recipients recounted their experiences to members of the PPI group and the science researchers.<h4>Results</h4>We subsequently asked both groups for individual, anonymised responses to the presentations, and we here present an analysis of that survey.<h4>Conclusions</h4>Overall, this exercise highlights different approaches to islet/SC-islet transplantation between people with lived experience of T1D and basic science diabetes researchers. This emphasises the continued need for open lines of communication between the two groups so each can benefit from the other's experience.","sourceUrl":"https://europepmc.org/article/MED/42666090","publicationTypes":["Review","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-08-29"},{"id":"42632545","doi":"10.1016/j.amjms.2026.08.018","title":"Distinguishing autoimmune recurrence from rejection in simultaneous pancreas-kidney transplantation recipients: a case-based short review.","source":"MED","abstract":"Simultaneous pancreas-kidney (SPK) transplantation provides durable glycemic control and survival benefit for selected patients with Type 1 diabetes and end-stage renal disease. Late-onset hyperglycemia after SPK is diagnostically challenging because pancreas graft dysfunction may reflect acute or chronic rejection, calcineurin inhibitor toxicity, vascular complications, post-transplant diabetes, or recurrent autoimmune type 1 diabetes (T1DR). Autoimmune recurrence occurs in a minority of recipients and is characterized by insulitis with selective beta-cell loss, often preceded by islet autoantibody conversion and progressive C-peptide decline. Distinguishing recurrence from rejection is clinically important because rejection may respond to intensified anti-rejection therapy, whereas established T1DR has no proven disease-modifying treatment. This case-based short review synthesizes current evidence on epidemiology, timing, maintenance immunosuppression, immunopathogenesis, genetic susceptibility, biomarkers, imaging, Banff-based histopathology, differential diagnosis, and management of recurrent autoimmune diabetes after SPK transplantation. A structured diagnostic approach integrating clinical timing, serology, metabolic testing, imaging, donor-specific antibody assessment, and pancreas biopsy with immunohistochemistry can help clinicians avoid both delayed recognition of recurrence and unnecessary escalation of immunosuppression.","sourceUrl":"https://europepmc.org/article/MED/42632545","publicationTypes":["Review","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-08-22"},{"id":"42608595","doi":"10.1007/s00125-026-06813-3","title":"A multi-centre study of belatacept and sirolimus for islet transplantation.","source":"MED","abstract":"<h4>Aims/hypothesis</h4>Islet transplantation is an appropriate treatment for selected individuals with type 1 diabetes mellitus and hypoglycaemia unawareness. The gold standard of maintenance immunosuppression to prevent allograft rejection is calcineurin inhibitor-based therapy; however, side effects warrant exploration of alternative immunosuppression. The co-stimulatory blocker belatacept and the mammalian target of rapamycin inhibitor sirolimus have demonstrated clinical benefit in solid organ transplantation, but efficacy in human islet transplantation is unknown.<h4>Methods</h4>We conducted a non-randomised, phase 2, multi-centre, open-label clinical study. Participants with type 1 diabetes receiving at least one islet transplant were treated with belatacept/sirolimus (bela/siro) and compared with a contemporaneous cohort treated with tacrolimus/mycophenolate mofetil (tac/MMF). The primary outcome was freedom from hypoglycaemia, with positive C-peptide and HbA<sub>1c</sub> <53 mmol/mol (7.0%) at 12 months after the first transplant. Secondary outcomes included metabolic control (Igls criteria, BETA-2 score), allosensitisation and changes in peripheral blood immune cell populations.<h4>Results</h4>Nine participants with type 1 diabetes received bela/siro, compared with 24 receiving tac/MMF. Eight participants (89%) receiving bela/siro achieved the primary outcome compared with 12 (52%) from the tac/MMF cohort. HbA<sub>1c</sub>, HYPO score and insulin requirements were reduced in both groups, although renal function remained unchanged only in the bela/siro group. Immunosuppression resulted in sustained suppression of all monocyte, NK, T and B cell subsets, although CD4<sup>+</sup>FOXP3<sup>+</sup> regulatory T cell proportions were higher in the bela/siro group.<h4>Conclusions/interpretation</h4>Baseline immunosuppression with bela/siro facilitated early islet engraftment and rates of insulin independence, with less impact on renal function, supporting the rationale for routine use in islet transplantation.<h4>Trial registration</h4>ANZCTR.org.au ACTRN12619000268145.","sourceUrl":"https://europepmc.org/article/MED/42608595","publicationTypes":["Clinical Trial, Phase II","research-article","Multicenter Study","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-08-17"},{"id":"42601420","doi":"10.1038/s41551-026-01775-8","title":"Biomimetic zona pellucida-encapsulated islets for sustained glycaemic control in immunocompetent mice.","source":"MED","abstract":"Islet transplantation is a promising therapy for treating type 1 diabetes. Thin capsules, although offering numerous advantages over thicker ones in islet transplantation, pose persistent challenges for ensuring long-term cell protection. Here we show a biomimetic approach for cell protection using thin capsules, inspired by the biological development of the zona pellucida. A thin 20-μm hydrogel capsule is spontaneously generated on the cell surface with 100% encapsulation efficiency through aptamer-directed molecular recognition, crosslinking and hardening. The entire encapsulation process takes place droplet-free and stress-free under physiological conditions, without exposure to harsh factors or any loss of cellular viability or function. Immunocompetent diabetic mice receiving encapsulated allogeneic islets achieved normoglycaemia, with most sustaining it for more than 100 days.","sourceUrl":"https://europepmc.org/article/MED/42601420","publicationTypes":["research-article","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-08-14"},{"id":"42570781","doi":"10.1016/j.actbio.2026.08.008","title":"Scalable 3D bioprinting of human islets in a pancreatic decellularized extracellular matrix-enriched bioink for beta-cell replacement therapy.","source":"MED","abstract":"Allogeneic cell transplantation such as beta-cell replacement for treatment of type 1 diabetes (T1D) is constrained by poor graft survival and functionality, immune rejection, and the lack of scalable biomanufacturing processes. Here, we engineered functional human islet constructs that replicate the physiomimetic human pancreatic microenvironment by employing a clinically-scalable 3D bioprinting system. To support human islet viability and function, we developed alginate-based bioinks incorporating human pancreatic decellularized extracellular matrix (dECM). These bioink formulations were optimized for shear-thinning properties for extrusion of human islets (HI), as well as selective permeability that supports nutrient and therapeutic molecule exchange. Extrusion-based printing parameters were refined to minimize shear stress-induced damage to human islets. The resulting bioprinted pancreatic constructs demonstrated robust structural integrity, high human islet viability (>85%), and long-term glucose-stimulated insulin secretion (GSIS) over a 21-days in vitro culture period, even at a high islet packing density (10,000 islet equivalent/mL) while free islet controls displayed a significant functional decline. The higher performance of bioprinted islets maybe attributable to the supportive 3D dECM-rich microenvironment mitigating culture-induced stress by recapitulating the islet pancreatic niche. This scalable 3D dECM-alginate bioprinted platform represents a new advanced functional material for advancing clinically translatable bio-artificial pancreas therapies for T1D. STATEMENT OF SIGNIFICANCE: Type 1 diabetes affects millions of people worldwide, yet cell-based therapies remain limited by poor graft survival and the lack of scalable manufacturing methods. This study introduces a clinically scalable 3D bioprinting strategy that embeds human pancreatic islets within a biomimetic, decellularized pancreas enriched bioink. Unlike previous approaches, this platform preserves islet viability and glucose-responsive insulin secretion over long-term culture, even at high, clinically relevant islet densities. By combining optimized bioprinting parameters with a pancreas-specific extracellular matrix, this work overcomes key trade-offs between printability, mass transport, and islet function. These findings represent an important step toward manufacturable, bioengineered pancreatic constructs for next-generation diabetes cell replacement therapies.","sourceUrl":"https://europepmc.org/article/MED/42570781","publicationTypes":["Journal Article"],"commentsCorrections":{"commentCorrection":[{"id":"40661431","type":"Update of","source":"MED","orderIn":1,"reference":"bioRxiv. 2025 Jun 10:2025.06.06.658360. doi: 10.1101/2025.06.06.658360."},{"id":"PPR1034707","note":"Link created based on a title-first author match","type":"Preprint in","source":"PPR","orderIn":10002}]},"firstPublicationDate":"2026-08-08"},{"id":"42598441","doi":"10.1016/j.bioactmat.2026.07.057","title":"Retrievable \"sea-island\" microstructured zwitterionic-silicone hydrogel devices: augmented oxygen transport and anti-fibrosis for sustaining islet survival.","source":"MED","abstract":"Islet encapsulation is a transformative strategy for type 1 diabetes (T1D) cellular therapy, enabling islet transplantation without lifelong immunosuppression. However, macroscale encapsulation faces prominent challenges: poor surgical retrieval, hypoxia, and foreign body response (FBR)-induced fibrosis, which severely compromise clinical translation. Herein, we develop a sea-island microstructured zwitterionic-silicone hydrogel device via copolymerization of siloxane monomer SiGMA, zwitterionic monomer carboxybetaine acrylamide (CBAA), and hydrogen-bonding monomer N-acryloyl glycinamide (NAGA). Notably, NAGA enhances hydrogel structural stability via strong H-bonds, reinforcing network and mechanical integrity to facilitate safe retrieval; importantly, NAGA's hydrogen bonding crosslinks allow the hydrogel device to be heat-sealed, preventing cell leakage and maintaining immunoisolation. The incorporation of SiGMA induces hydrophobic phase separation, generating silicone-rich polymer microdomains that enhance oxygen permeability to alleviate islet hypoxia, while zwitterionic CBAA significantly improves antifouling performance and mitigates fibrotic encapsulation by suppressing the host FBR. After 8 weeks of implantation in mice and beagle dogs, the device exhibits minimal fibrotic encapsulation and can be readily retrieved. Notably, even without pre-vascularization or immunosuppression, the transplanted islets in diabetic mice sustain normoglycemia for up to 400 days. These results demonstrate a robust retrievable encapsulation device that addresses key bottlenecks in islet transplantation, advancing its potential translation for T1D.","sourceUrl":"https://europepmc.org/article/MED/42598441","publicationTypes":["research-article","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-08-04"},{"id":"42240469","doi":"10.2337/db26-0149","title":"Nanofibrous Bioabsorbable Functionalized Scaffolds Augment Subcutaneous Islet Engraftment and Function in Mice.","source":"MED","abstract":"The subcutaneous (SQ) space is a promising site for islet transplantation to treat type 1 diabetes. We hypothesize that nanofibrous bioabsorbable functionalized scaffolds (BAFS) implanted in the SQ space will create a highly vascularized niche that will support islet engraftment. Electrospun poly(lactic-co-glycolic acid) (PLGA) and gelatin (G) (PLGA + G) scaffolds functionalized with vascular endothelial growth factor (V) and laminin (L) were wrapped around a nylon catheter and implanted into the SQ space of immunodeficient mice. Experimental groups included PLGA, PLGA + G, PLGA + G + V + L, and the device-less catheter alone. The degree of vascularization in these sites was assessed 4 weeks after implantation, and in a separate cohort of mice, neonatal porcine islets (NPIs) were transplanted subcutaneously into diabetic mice. NPIs transplanted under the kidney capsule served as controls. PLGA + G + V + L recipients showed enhanced vascularization, with a higher number of cells positive for lectin, smooth muscle actin, and CD31 compared with other groups (P < 0.05). Recipients of PLGA + G + V + L scaffolds and NPIs achieved normoglycemia faster (P < 0.05) and exhibited higher serum porcine insulin levels (P < 0.05) compared with all other groups. Our nanofibrous BAFS (PLGA + G + V + L) significantly vascularized the SQ space and supported long-term islet graft survival, suggesting a clinically relevant and tunable alternative site for β-cell replacement therapies.<h4>Article highlights</h4>This study highlights how bioabsorbable functionalized scaffolds (BAFS) create a subcutaneous vascularized niche that supports islet graft function. BAFS exhibit sustained release of vascular endothelial growth factor and laminin, which promoted enhanced vascularization in the subcutaneous space. Additionally, these vessels are mature and patent as evidenced by intraluminal cells positive for lectin and smooth muscle actin. BAFS transplanted with neonatal porcine islets achieved normoglycemia faster and exhibited higher serum porcine insulin levels than all other groups. Overall, BAFS transplanted with neonatal porcine islets facilitates long-term islet graft function and corrects diabetes in mice, suggesting a clinically relevant and tunable alternative site for β-cell replacement therapies.","sourceUrl":"https://europepmc.org/article/MED/42240469","publicationTypes":["Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-08-01"},{"id":"42613697","doi":"10.2174/0127722708449951260724061020","title":"Regenerative Approaches in Type 1 Diabetes: β-cell Replacement and Emerging Therapeutics.","source":"MED","abstract":"Type 1 diabetes (T1D) is a selective autoimmune loss of insulin-secreting pancreatic β-cells and lifelong replacement with exogenous insulin. The disease remains incurable despite extensive research. New therapies, such as stem cell replacement, have been developed as the leading β-cell replacement modality. Pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) have been established as insulin-secreting cells, a theoretically unlimited reservoir for transplantation. Defective β-cell function, immune rejection, and ethical issues still exist. New immunosuppressive measures such as costimulation blockade therapy or regulatory T cell (Treg)-based therapy have been proposed to optimize graft survival with fewer side effects. Bioengineered islet grafting, xenograft transplantations, and gene editing tools are also analyzed in order to improve the effectiveness of β-cell replacement. Therapeutic advances in target immunomodulation and islet encapsulation are also enhancing survival and functionality of transplanted cells. This article provides a pharmaceutical review of emerging β-cell replacement therapies including stem cell-derived therapy, immunotherapy, and innovative biotechnologybased solutions. Breaking through current limitations of these therapies is crucial to achieving long-term insulin independence for T1D patients. Refining differentiation protocols, improving immune evasion strategies, and merging paradigms of personalized medicine are essential to achieving maximal therapeutic benefit in future studies.","sourceUrl":"https://europepmc.org/article/MED/42613697","publicationTypes":["Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-07-31"},{"id":"42425151","doi":"10.1088/1748-605x/ae88a4","title":"High-density microwell arrays enable controlled pseudoislet engineering for diabetes cell therapy.","source":"MED","abstract":"Macroencapsulation systems for pancreatic islet delivery are an emerging strategy for cell replacement therapy in type 1 diabetes, aimed at eliminating systemic immunosuppression and enabling the use of alternative cell sources. A critical design challenge is to achieve high packing densities while maintaining sufficient oxygen and nutrient supply to ensure islet viability and function. This design-focused study presents a one-step method for the simultaneous and defined formation and spatial arrangement of uniformly sized pancreatic pseudoislets using high-density concave microwell arrays with potential for future integration into macroencapsulation devices. Microwells with diameters between 130 and 200 µm were arranged in a hexagonal pattern with inter-well spacings of 50 or 100 µm to maximize the packing density while maintaining separation between clusters. The effects of microwell depth, diameter, and inter-well spacing on pseudoislet size, morphology, viability, and glucose-stimulated insulin secretion were systematically evaluated using reaggregated rat islet cells as a standardized and well-characterized model system under normoxic and hypoxic conditions. The optimized microwell configuration enabled efficient pseudoislet formation with a tailorable, uniform size, high viability, and preserved insulin secretory function, even at high densities. This scalable microwell array technology addresses key limitations of current pseudoislet culture and transplantation methods, thus providing a base for improved macroencapsulation device design in diabetes cell therapy.","sourceUrl":"https://europepmc.org/article/MED/42425151","publicationTypes":["Research Support, Non-U.S. Gov't","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-07-30"},{"id":"42476259","doi":"10.1016/j.ando.2026.102591","title":"Rebuilding Beta-Cell Function: Advances In Replacement, Preservation And Regeneration.","source":"MED","abstract":"Since the life-saving discovery of insulin in 1921, multiple approaches have been developed to improve long-term outcomes in patients with type 1 diabetes (T1D). While technological advance such as closed-loop insulin delivery systems are now well known to most endocrinologists, biological approaches to restore beta-cell mass remain less widely recognized but are rapidly evolving. Since 2021, islet transplantation has been covered by the French national health insurance system. Nevertheless, islet allotransplantation requires complex isolation procedures from brain-dead donors, limiting access to a sufficient islet mass and requiring lifelong immunosuppression. Therefore, alternative strategies have been developed to restore the beta-cell pool: preservation of residual beta cells, or regeneration. A major advance in beta-cell preservation was the marketing authorization of teplizumab by the FDA (2022) and the European Medicines Agency (2025). This anti-CD3 monoclonal antibody has been shown to delay the onset of clinical T1D in individuals with stage 2 disease. Beta-cell regeneration encompasses several approaches: differentiation from stem cells, proliferation of existing beta cells, dedifferentiation, neogenesis from ductal cells, and transdifferentiation of endocrine, exocrine or extra-pancreatic cells. Three of these pathways led to major breakthroughs in 2025. Firstly, insulin independence under immunosuppression was achieved at 1 year in 83% of patients after intraportal transplantation of human embryonic stem-cell-derived islets. Secondly, insulin independence was reported in China in individual cases following transplantation of autologous chemically induced pluripotent stem-cell-derived islets or allogeneic stem-cell-derived islets. And thirdly, stable human C-peptide production was observed 12 months after intra-muscular transplantation of engineered hypoimmune islets without immunosuppression. The present review summarizes these recent advances, from experimental models to clinical applications, opening up new perspectives for cell-based therapies in T1D.","sourceUrl":"https://europepmc.org/article/MED/42476259","publicationTypes":["Review","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-07-20"},{"id":"42426563","doi":"10.1111/dom.71054","title":"Continuous Intraperitoneal Insulin Infusion for People With Type 1 Diabetes: A Literature Review and International Position Statement.","source":"MED","abstract":"Achieving glucose targets without hypoglycaemia is the treatment goal in type 1 diabetes. Structured education, intensified insulin injection regimens, continuous glucose monitoring, automated insulin delivery, and ongoing support from a multidisciplinary team all support people with type 1 diabetes to achieve this goal. Despite these advances, significant barriers to achieving optimal management remain. Continuous intraperitoneal insulin infusion has comparable or better glucose outcomes to continuous subcutaneous insulin infusion and may reduce the frequency of hypoglycaemia, including severe episodes. Intraperitoneal insulin may be considered as a treatment modality for children and adults with type 1 diabetes using optimised intensive insulin therapy for whom subcutaneous insulin has failed due to lipoatrophy, -dystrophy or -hypertrophy, local allergy, subcutaneous insulin resistance or co-existing skin conditions. Failure of subcutaneous insulin may result in recurrent or unexplained severe hypoglycaemia or hyperglycaemia. Intraperitoneal insulin may also be considered as a treatment modality for people with type 1 diabetes with severe needle-phobia, and for those being considered for islet cell or pancreatic transplantation, or where transplantation is not available. This paper summarises current intraperitoneal insulin delivery technology, its potential risks and benefits, and an expert position statement. It is intended for use by diabetes specialist healthcare professionals, and as a reference for other healthcare professionals, commissioners, payors, people with diabetes, their carers, and advocates.","sourceUrl":"https://europepmc.org/article/MED/42426563","publicationTypes":["review-article","Review","Consensus Statement","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-07-09"},{"id":"42404286","doi":"10.1097/txd.0000000000001960","title":"Eye Health Among Islet Cell Transplant Recipients With Long-duration Type 1 Diabetes.","source":"MED","abstract":"<h4>Background</h4>Diabetic retinopathy (DR) is the commonest cause of blindness among people with type 1 diabetes (T1D) and can progress over time. In Australia, islet cell transplantation (ICT) is available for adults with T1D experiencing recurrent severe hypoglycemia. Rapid improvement in glycemia, which can occur post-ICT, may lead to \"early worsening\" of DR and warrants investigation. This study explored eye health outcomes among ICT recipients.<h4>Methods</h4>This retrospective study examined all ICT recipients at a single tertiary institution in Victoria, Australia, 2007-2022 inclusive. Recipients of successful ICT, with available eye health information pre- and posttransplantation, were included. Eye health outcomes were assessed relative to ICT for changes in DR and other major retinal pathologies.<h4>Results</h4>Sixteen recipients (30 eyes) with T1D duration median 31 y (interquartile range, 26-44) were followed up for 5 y (interquartile range, 4-9). At 12 mo post-ICT, hemoglobin A<sub>1c</sub> improved by -1.2 percentage points (-1.9 to -0.5; <i>P</i> < 0.001). Pre-ICT, 9 of 16 recipients (56%) had DR, with 4 recipients having proliferative DR. During follow-up post-ICT, 4 of 16 recipients (25%) had worsening eye outcomes; there were no new cases of proliferative DR. Four recipients had \"early worsening\" signs, not associated with progression of DR. Recipients experiencing worsening eye outcomes post-ICT exhibited higher hemoglobin A<sub>1c</sub> and lower C-peptide levels during 12 mo compared with recipients who had stable eye outcomes (<i>P</i> = 0.02 and <i>P</i> = 0.01, respectively).<h4>Conclusions</h4>These findings highlight the potential positive impact of ICT to stabilize eye health among a small group of ICT recipients with long-duration type 1 diabetes. An extended systematic evaluation of eye health pre- and post-ICT is required to monitor both short-term and long-term eye health among transplant recipients.","sourceUrl":"https://europepmc.org/article/MED/42404286","publicationTypes":["research-article","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-07-02"},{"id":"42542743","doi":"10.7759/cureus.111930","title":"Cell-Based Therapies for Type 1 Diabetes: A Narrative Review of Stem Cell-Derived Islets, Encapsulation Strategies, and Recent Clinical Trials.","source":"MED","abstract":"Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells, necessitating lifelong insulin therapy. While islet transplantation has demonstrated efficacy in restoring glycemic control, donor scarcity and the requirement for chronic immunosuppression limit its widespread application. Recent advances in stem cell biology, bioengineering, and immunomodulation have catalyzed a paradigm shift toward stem cell-derived β-cell replacement therapies. This narrative review presents recent clinical trials and technological innovations in cell-based therapies for T1D, with particular emphasis on stem cell-derived islet generation, encapsulation strategies for immunoprotection, and emerging clinical evidence. Landmark clinical trials and pioneering work with chemically induced pluripotent stem cells have demonstrated proof-of-concept for insulin independence and glucose-responsive C-peptide secretion. Encapsulation technologies, ranging from macroencapsulation devices to microencapsulation with bioactive materials, aim to eliminate the need for systemic immunosuppression while protecting grafts from immune rejection. Despite promising early results, challenges including fibrosis, vascularization, long-term graft survival, and scalable manufacturing remain. This review provides a comprehensive overview of the current state of cell-based therapies for T1D and outlines future directions for translating these innovations into routine clinical practice.","sourceUrl":"https://europepmc.org/article/MED/42542743","publicationTypes":["review-article","Review","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-07-01"},{"id":"42511958","doi":"10.3390/biomedicines14071481","title":"siRNA-Mediated Reduction of Apolipoprotein CIII Delays Pancreatic Islet Deterioration and Onset of Type 1 Diabetes in Diabetes-Prone BioBreeding Rats.","source":"MED","abstract":"<b>Background/Objectives</b>: Type 1 diabetes (T1D) is an autoimmune disease characterized by progressive β-cell loss. Apolipoprotein CIII (apoCIII), a lipid metabolism regulator, is elevated in T1D and implicated in β-cell apoptosis. Antisense oligonucleotide-mediated apoCIII reduction delays diabetes onset in diabetes-prone BioBreeding (DPBB) rats. This study examined whether small-interfering RNA (siRNA) targeting apoCIII during the final prediabetic month preserves islet integrity and delays T1D onset. <b>Methods</b>: Two siRNAs targeting rat apoCIII were evaluated in 30-day-old DPBB rats for efficacy and off-target effects. Hepatic and plasma apoCIII levels were measured, and neighboring apolipoprotein gene expression was assessed. The most specific candidate (apoCIII-siRNA2) was selected. Duration of action was determined after a single injection. To study the effects of apoCIII-lowering treatment in vivo, islets from 25-day-old DPBB rats were transplanted into the anterior chamber of the eye of age-matched DPBB recipients. Rats received weekly intravenous injections of apoCIII-siRNA2 from day 30 until diabetes onset. Islet morphology, vascularization, and phagocyte infiltration were assessed by confocal imaging three and five weeks post-transplantation. <b>Results</b>: Both siRNAs reduced apoCIII, but one showed off-target effects and was excluded. A single injection of apoCIII-siRNA2 suppressed plasma apoCIII for approximately one week and weekly treatment maintained low circulating apoCIII levels. Five weeks after transplantation islet morphology and vascularization were preserved, and there was no increase in phagocyte infiltration. This resulted in a delayed onset of diabetes. <b>Conclusions</b>: siRNA-mediated apoCIII reduction delays pancreatic islet deterioration and T1D onset in DPBB rats, supporting apoCIII as a contributing factor to β-cell vulnerability and thereby a potential therapeutic target.","sourceUrl":"https://europepmc.org/article/MED/42511958","publicationTypes":["research-article","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-06-30"},{"id":"42440699","doi":"10.3389/fmolb.2026.1825364","title":"Molecular diagnostics in pancreas transplantation: past, present, and future.","source":"MED","abstract":"Pancreas transplantation is the gold standard endocrine replacement therapy for patients with type 1 diabetes (T1D) and chronic kidney disease. Histological assessment remains the cornerstone for diagnosing pancreas graft rejection, relying on the Banff classification to standardize interpretation. Transcriptomic analyses have transformed transplantation research by enabling gene expression profiling within allografts. Studies utilizing bulk RNA (RNA-seq) and single-cell RNA sequencing (scRNA-seq) have advanced understanding of immune-mediated graft injury. However, pancreas transplantation research remains limited by small single-center cohorts, while extrapolation from other solid organ transplants is constrained by the unique structural and functional characteristics of the pancreas graft. These challenges partially arise from the distinct compartments involved in major pancreas allograft pathologies, including exocrine injury in alloimmune-rejection response and endocrine islet injury in a myriad of post-transplant beta cell stressors (i.e., T1D recurrence, CNI-toxicity, or metabolic syndrome). The application of molecular diagnostics in pancreas transplant biopsies has been demonstrated, including clinical-grade microarray technology. Nevertheless, pancreas-specific gene expression markers remain underexplored, and robust evidence regarding their clinical utility is lacking. This review conceptualizes pancreas allograft injury as a dual-compartment process involving both exocrine rejection and endocrine islet injury, thereby providing an interpretive framework for evaluating emerging molecular diagnostics in pancreas transplantation.","sourceUrl":"https://europepmc.org/article/MED/42440699","publicationTypes":["review-article","Review","Journal Article"],"commentsCorrections":null,"firstPublicationDate":"2026-06-22"}],"hitCount":2503},"retrievedAt":"2026-10-19T18:17:36.242Z","reviewedBaseline":{"id":"t1d-restoration-reference-2026-10-19","scope":"Targeted review of the requested China reports and a no-immunosuppression proof of concept. Not an exhaustive or continuously updated literature review.","references":[{"id":"cipsc-2024","doi":"10.1016/j.cell.2024.09.004","url":"https://doi.org/10.1016/j.cell.2024.09.004","use":"Cell-restoration evidence, not a no-immunosuppression benchmark.","pmid":"39326417","title":"Autologous CiPSC-derived islets: one-year T1D report","finding":"One participant achieved sustained insulin independence starting 75 days after transplantation; the paper reports one-year follow-up.","unresolved":"Patient-level longitudinal measurements and immunosuppression details must be extracted from the full report before calibration.","sourceLevel":"Primary publication abstract retrieved through Europe PMC; immunosuppression context corroborated by indexed reporting.","immuneContext":"The recipient was already receiving immunosuppression for a prior liver transplant. This case cannot establish efficacy without systemic immunosuppression.","supportingUrl":"https://www.nature.com/articles/d41586-024-03129-3","publicationYear":2024},{"id":"e-islets-2026","doi":"10.1016/S2213-8587(25)00423-1","url":"https://doi.org/10.1016/S2213-8587(25)00423-1","use":"Challenge the assumption that replacement alone solves T1D. Treat withdrawal observations as non-randomized, not a measured causal killing rate.","pmid":"41765034","title":"Autologous and allogeneic E-islets in three T1D recipients","finding":"The institute reports restored islet function in a three-recipient series with differing outcomes and immune regimens. It describes insulin independence in an allogeneic recipient under standard immunosuppression.","unresolved":"Full-paper trajectories, regimen timing, assay limits, and confounders are needed before fitting. Do not merge this T1D series with the earlier T2D report.","sourceLevel":"Publication identity confirmed through Europe PMC; clinical details read in the originating institute report, not the full paper.","immuneContext":"The institute describes loss of graft beta-cell function after an autologous recipient stopped immunosuppression. Autologous origin did not remove the recurrent-autoimmunity problem in this report.","supportingUrl":"https://cemcs.cas.cn/kyjz/202602/t20260226_8145958.html","publicationYear":2026},{"id":"e-islets-manufacturing","url":"https://english.cas.cn/newsroom/cas-in-media/202603/t20260318_1152861.shtml","use":"Manufacturing and regulatory context only; not a clinical efficacy parameter.","title":"E-islet manufacturing and regulatory reports","finding":"CAS reports shortening the cultivation stage from 40 days to 14 days. The originating institute reports Chinese trial clearance in April 2025 and US IND clearance in January 2026 for E-islet 01.","unresolved":"A 2029 market-approval date remains an unverified projection. The 14-day claim is not the complete patient-to-product manufacturing timeline.","sourceLevel":"Institutional reporting. No regulator-issued clearance documents independently retrieved.","immuneContext":"Manufacturing speed and trial authorization do not establish immune protection, insulin independence without suppression, or zero tumor risk.","supportingUrl":"https://cemcs.cas.cn/kyjz/202602/t20260226_8145958.html","publicationYear":2026},{"id":"hypoimmune-2025","doi":"10.1056/NEJMoa2503822","url":"https://doi.org/10.1056/NEJMoa2503822","use":"A separate protection proof of concept, not a substitute for a full-function endpoint.","pmid":"40757665","title":"Survival of transplanted allogeneic beta cells with no immunosuppression","finding":"One recipient with long-standing T1D had glucose-responsive secretion from gene-edited donor islets without immunosuppressive drugs over the reported 12-week interval.","unresolved":"Later follow-up, independent recipients and adequate functional capacity require separate evidence.","sourceLevel":"Primary report read from a publicly accessible copy.","immuneContext":"This report addresses graft protection without systemic immunosuppression, but did not establish insulin independence or a durable functional cure.","supportingUrl":"https://gwern.net/doc/genetics/editing/2025-carlsson.pdf","publicationYear":2025}],"reviewedOn":"2026-10-19"}},"createdAt":"2026-10-19T18:17:36.246Z","stale":false,"refreshIntervalHours":24}}