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Aims/hypothesis: Insulitis, a hallmark of inflammation preceding autoimmune type 1 diabetes, leads to the eventual loss of functional beta cells. 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., Methods: CD4 + 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-1β, TNF-α, IFN-γ) for 24-48 h in the presence of vehicle or increasing concentrations of the CB1R blocker JD-5037. Expression of CNR1 (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., Results: CNR1 expression was upregulated in circulating CD4 + 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., Conclusions/interpretation: 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., Data Availability: Transcriptomic analysis of sorted human beta cells are from Gene Expression Omnibus database, accession no. GSE121863, available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM3448161 ., (© 2024. The Author(s).)

Objective: To describe the epidemiological behavior of Guillain-Barré syndrome (GBS) in Peru., Materials and Methods: Descriptive study of secondary data on the Ministry of Health (MINSA) hospital discharges during the period 2012-2017; EsSalud and SuSalud hospital discharges between 2015 and 2017; and national mortality data between 2014-2016. The identification of GBS in the databases was carried out using the International Classification of Diseases, 10th version, by means of code G610. Incidence, fatality rate, and mortality were estimated by age, sex, and department group., Results: A total of 955 cases of GBS were identified in the database of MINSA hospital discharges between 2012 and 2017, with a higher frequency in men, within the 20 to 59-year old population. The national incidence of GBS per 100,000 inhabitants was 0.62 (2015), 0.92 (2016), and 0.91 (2017), being higher in older adults and in men. The overall case fatality rate was 3.5%, and was highest in those over 60. The average length of hospitalization was 16 ± 22 days. In addition, Lima is the department that accounted for more than 40% of all GBS cases; and Cusco, Lima, Callao, Lambayeque, and Arequipa had the highest incidence., Conclusions: This study provides relevant information to better understand the epidemiological behavior of GBS in Peru, and thus ensure adequate patient care nationally.