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However, functional beta cells can persist even in the face of continuous insulitis. Despite advances in immunosuppressive treatments, maintaining functional beta cells to prevent insulitis progression and hyperglycaemia remains a challenge. The cannabinoid type 1 receptor (CB1R), present in immune cells and beta cells, regulates inflammation and beta cell function. Here, we pioneer an ex vivo model mirroring human insulitis to investigate the role of CB1R in this process.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>CD4<jats:sup>+<\/jats:sup> T lymphocytes were isolated from peripheral blood mononuclear cells (PBMCs) from male and female individuals at the onset of type 1 diabetes and from non-diabetic individuals, RNA was extracted and mRNA expression was analysed by real-time PCR. Single beta cell expression from donors with type 1 diabetes was obtained from data mining. Patient-derived human islets from male and female cadaveric donors were 3D-cultured in solubilised extracellular matrix gel in co-culture with the same donor PBMCs, and incubated with cytokines (IL-1\u03b2, TNF-\u03b1, IFN-\u03b3) for 24\u201348 h in the presence of vehicle or increasing concentrations of the CB1R blocker JD-5037. Expression of <jats:italic>CNR1<\/jats:italic> (encoding for CB1R) was ablated using CRISPR\/Cas9 technology. Viability, intracellular stress and signalling were assayed by live-cell probing and real-time PCR. The islet function measured as glucose-stimulated insulin secretion was determined in a perifusion system. Infiltration of immune cells into the islets was monitored by microscopy. Non-obese diabetic mice aged 7 weeks were treated for 1 week with JD-5037, then euthanised. Profiling of immune cells infiltrated in the islets was performed by flow cytometry.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>\n              <jats:italic>CNR1<\/jats:italic> expression was upregulated in circulating CD4<jats:sup>+<\/jats:sup> T cells from individuals at type 1 diabetes onset (6.9-fold higher vs healthy individuals) and in sorted islet beta cells from donors with type 1 diabetes (3.6-fold higher vs healthy counterparts). The peripherally restricted CB1R inverse agonist JD-5037 arrested the initiation of insulitis in humans and mice. Mechanistically, CB1R blockade prevented islet NO production and ameliorated the ATF6 arm of the unfolded protein response. Consequently, cyto\/chemokine expression decreased in human islets, leading to sustained islet cell viability and function.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\/interpretation<\/jats:title>\n            <jats:p>These results suggest that CB1R could be an interesting target for type 1 diabetes while highlighting the regulatory mechanisms of insulitis. Moreover, these findings may apply to type 2 diabetes where islet inflammation is also a pathophysiological factor.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Data availability<\/jats:title>\n            <jats:p>Transcriptomic analysis of sorted human beta cells are from Gene Expression Omnibus database, accession no. GSE121863, available at <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSM3448161\" ext-link-type=\"uri\">https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSM3448161<\/jats:ext-link>.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s00125-024-06193-6","type":"journal-article","created":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T15:01:55Z","timestamp":1718204515000},"page":"1877-1896","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pharmaceutical targeting of the cannabinoid type 1 receptor impacts the crosstalk between immune cells and islets to reduce insulitis in 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Some of the figures were created using Servier Medical Art templates. We thank the Diabetes Unit of the Regional University Hospital of Malaga and the Endocrinology, Diabetes, Obesity, and Nutrition team at IBIMA-Plataforma BIONAND SSPA (Spain) (G. Rojo, R. El Bekay, S. Garcia Serrano, E. Garcia Escobar, A. Lago, C. Maldonado, A. Gentile, S. Hamyani, Juan M. Gomez Zumaquero) for their constant support and valuable input. We thank T. Diaz Cordoba, coordinator of the Andalusian Health System Biobank at IBIMA-Plataforma BIONAND (Spain) for her constant help. We thank the Biotherapy Platform at CHU of Lille (France) for the isolation of the islets from cadaveric donors used in this study and for their contribution to the evaluation of the islets. We thank B. Legendre at UMR1190, Inserm (France) and L. Antelo, M. J. Palomo and I. Mena at IBIMA-Plataforma BIONAND (Spain) for their support in the legal framework and management of the study. We thank the team at the animal facility of the University of Malaga (Spain), for contributing to the welfare of the animals used in this study.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"Transcriptomic analysis of sorted human beta cells are available at Gene Expression Omnibus database, accession no. GSE121863, available at . The data from the study in humans are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at IBIMA-Plataforma BIONAND and Inserm UMR1190, CHU of Lille.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This study was funded by the Consejeria de Salud y Familias of Andaluc\u00eda (PI-0318-2018), the project PID2021-128926OA-I00 was funded by MICIU\/AEI\/10.13039\/501100011033 and UE, the Ministry of Science and Innovation (PID2021-128926OA-I00), the Spanish Diabetes Society (Sociedad Espanola de Diabetes, SED; CPC22133) and Agence Nationale de la Recherche (Laboratoire d\u2019excellence European Genomic Institute for Diabetes under grant ANR-10-LABX-0046). IG-M and F-JB-S were funded by the Junta de Andaluc\u00eda (Nicolas Monardes program; C1-0018-2019 and C-0070-2012, respectively). CIBERDEM is an initiative of the Instituto de Salud Carlos III, Madrid, Spain. JME was supported by the Intramural Research Program of the National Institute on Aging\/NIH. IG-M was supported by Inserm.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"A patent application based on this work has been filed. IG-M, F-JB-S and MSRdA are the inventors of this patent. The other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"IG-M conceptualised and supervised the study and obtained funding. JME contributed to the conceptualisation of the study. EW, SH, VG, AC, MGD, LSS and IG-M performed experiments, and acquired, analysed and interpreted data. MSRdA, ICBE, MJVH, FL, F-JB-S, GO and NC acquired and\/or analysed and\/or interpreted data related to the clinical study. MC, GP, ND, JTh, CB, JK-C and FP acquired and\/or analysed and\/or interpreted data related to the human ex vivo study. SH contributed to the design and construction of CRISPR\/Cas9 and AAVs, and LH and JTa acquired and\/or analysed and\/or interpreted data related to the lipidomic study. IG-M and EW performed the formal analysis. IG-M wrote the manuscript. All authors reviewed the article critically and approved the final manuscript. IG-M is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}