Background and purpose: Cannabidiol (CBD) and cannabigerol (CBG) are non-psychoactive phytocannabinoids with emerging therapeutic potential in metabolic dysfunction-associated steatotic liver disease (MASLD). However, the molecular mechanisms underlying their beneficial effects remain incompletely understood. In this study, we assessed the metabolomic and lipidomic impact of CBD and CBG in a mouse model of diet-induced obesity and MASLD.

Experimental approach: Male C57Bl/6 mice fed on a high-fat diet for 14 weeks were treated for 4 weeks with daily intraperitoneal CBD, CBG or vehicle. Assessments included body composition, indirect calorimetry, glucose tolerance, serum biochemistry and VLDL-triglyceride profiling. Hepatic mechanisms were examined by metabolomics, lipidomics, creatine kinase activity, cathepsin activity-based probes and gene/protein expression, with a choline-deficient diet cohort to test phospholipid-dependence of CBG.

Key results: CBD or CBG treatment improved glycaemic control, reduced hepatic triglycerides and normalised serum lipids, without affecting energy expenditure. Metabolomics revealed increased hepatic phosphocreatine and creatine with enhanced creatine kinase activity, indicating phosphocreatine-based energy buffering independent of fatty acid oxidation changes. Lipidomics showed reduced triglycerides and ceramides, with increased phospholipids and lysobisphosphatidic acids, correlating with restored hepatic cathepsin activity and improved lysosomal lipid degradation. CBG was ineffective in choline-deficient MASLD, indicating phospholipid pathway dependence.

Conclusions and implications: These findings identify a novel, endocannabinoid system-independent mechanism by which CBD and CBG enhance hepatic energy buffering and lysosomal function, contributing to improved liver lipid handling and supporting phytocannabinoids as promising MASLD therapeutics.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation, inflammation, and metabolic dysregulation. The endocannabinoid system (ECS), particularly the cannabinoid-1 receptor (CB1R), regulates renal metabolism and inflammatory signaling, yet its role in ADPKD remains largely unexplored. METHODS: We analyzed publicly available human kidney transcriptomic datasets (bulk microarray GSE7869; single-nucleus RNA-sequencing from ADPKD GSE185948, and diabetic kidney disease cohorts GSE195460) and validated findings in ADPKD patient kidney tissue versus non-cystic controls using quantitative PCR, liquid chromatography-tandem mass spectrometry, and Western blotting. Longitudinal disease progression was evaluated in Pkd1RC/RC mice at 3, 6, 9, and 12 months, with comprehensive assessment of ECS components, endocannabinoid (eCB) levels, and kidney function parameters. Correlation examined associations between ECS markers and disease severity. RESULTS: Human ADPKD kidneys demonstrated consistent upregulation of CNR1 transcripts across platforms, with single-nucleus analysis revealing enrichment in proximal tubule-derived populations including failed-repair proximal tubule cells. ADPKD tissue exhibited significant reductions in key ECS-metabolizing enzymes (FAAH, NAPEPLD, MGLL) and marked depletion of eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG). In contrast, diabetic kidney disease showed minimal ECS alterations, indicating ADPKD-specific dysregulation. Pkd1RC/RC mice recapitulated human findings, with Cnr1 upregulation beginning at 6 months and significant AEA/N-oleoylethanolamine (OEA) depletion at 9–12 months. CB1R protein elevation preceded ligand depletion, suggesting progressive receptor sensitization. Correlation analyses revealed robust associations between CB1R/enzyme expression, eCB depletion, and declining kidney function (kidney weight-to-body weight ratio, blood urea nitrogen, and creatinine clearance). CONCLUSIONS: ADPKD kidneys exhibit disease-specific dysregulation of the ECS, characterized by increased CB1R expression accompanied by paradoxical depletion of eCB ligands. These alterations correlate with cyst burden and functional decline across human and murine disease stages, identifying the ECS as a prominently affected pathway during ADPKD progression. While our findings establish a strong association between ECS dysregulation and disease severity, whether altered CB1R signaling represents a causal driver of cystogenesis or a secondary, yet therapeutically targetable component of the cystic and injury response will require direct genetic or pharmacologic modulation of CB1R/ECS signaling.

Background:

The endocannabinoid system (ECS) regulates homeostasis, inflammation, and organ-specific function. In the kidney, ECS activity modulates renal hemodynamics, and its overactivation is linked to chronic injury. However, the importance of the ECS involvement in acute kidney injury (AKI) remains unclear. This study aimed to characterize changes in circulating endocannabinoid (eCB) levels before and after relief of upper urinary tract obstruction (UUTO), to better understand ECS dynamics during acute renal dysfunction. These findings may inform the development of novel biomarkers and therapeutic targets for renal injury.

Objectives:

To characterize changes in circulating eCB levels before and after relief of UUTO, and to compare responses between patients with and without AKI.

Design:

Prospective observational cohort with paired, within-person sampling.

Methods:

Patients presenting to the emergency department with acute renal colic due to obstructive urolithiasis who underwent kidney decompression within 24 h were prospectively enrolled. Clinical, laboratory, and imaging data plus paired blood samples for eCB analysis were collected pre and post-drainage. Patients were divided into two groups: those who had AKI at presentation, and non-AKI controls. Serum eCBs were quantified, and fold changes compared using nonparametric analysis.

Results:

Twenty-two patients enrolled (10 had AKI and 12 served as non-AKI controls). Serum N-acylethanolamines (NAEs) showed divergent responses between the two groups. In AKI, N-arachidonoylethanolamine (AEA), N-palmitoylethanolamine, and N-oleoylethanolamine increased following drainage (p = 0.06, 0.008, 0.08). In contrast, patients without AKI demonstrated a reduction in NAE levels, with a significant AEA drop (p = 0.03) after obstruction relief. Notably, the fold-change in NAE levels post-drainage was significantly higher in patients with AKI compared to those without AKI.

Conclusion:

Circulating NAEs increase following relief of obstruction in patients with acute renal dysfunction, suggesting a potential role for ECS activation in the pathophysiology of UUTO-induced kidney injury. These findings highlight the ECS as a promising target for further investigation as a possible therapeutic avenue in AKI.

Δ⁹-Tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, is widely recognized for its central effects mediated by cannabinoid receptors. Here, we uncover a distinct peripheral mechanism by which THC inhibits the excitability of nociceptive neurons. We show that THC directly targets the nociceptive voltage-gated sodium channels Na_V1.7 and Na_V1.8 through the conserved local anesthetic binding site. This interaction reduces sodium currents and suppresses action potential generation in peripheral sensory neurons. Our findings demonstrate that, beyond its central psychoactivity, THC exerts direct peripheral nociceptor inhibition via modulation of Na_V1.7 and Na_V1.8, offering new insight into cannabinoid-based analgesia independent of cannabinoid receptor signaling.

Objectives

Obesity-induced steatotic liver disease (SLD) is driven by the uptake of adipocyte-derived fatty acids (FAs) into hepatocytes via the FA translocase CD36, which also prevents their consumption by inhibiting AMP kinase (AMPK)-mediated FA oxidation (FAO). We explored the role of hepatocyte CB1 receptors (hCB1R) in controlling hepatic triglyceride (TG) content by regulating CD36 and its downstream targets.

Methods

hCB1R knockout (hCB1Rko) mice and their control littermates kept on standard or high-fat diet were used to analyze hCB1R-mediated hepatic gene expression profile and lipid metabolism in intact mice and in cultured hepatocytes.

Results

Multi-omics data indicate that hCB1R target a distinct set of genes associated with SLD, including Cd36. In mice with diet-induced obesity, hCB1R signaling via CD36-AMPK-FAO pathway contributes to both the development of SLD and its reversal by CB1R blockade. But, in lean mice hCB1R signaling inhibits CD36 expression and activates AMPK-mediated FAO. These opposite effects were replicated in AML12 mouse hepatocytes incubated with or without oleic acid (OA). OA, an endogenous ligand of GPR3, induced a switch in hCB1R signaling from a Gi/oα-mediated reduction in cAMP to a Gsα-mediated increase in cAMP in a GPR3/Gsα -dependent manner, facilitated by increasing the ratio of Gsα:Gi/oα proteins in the steatotic compared to lean liver.

Conclusions

In the lean state, endocannabinoid activation of hCB1R increases FAO, which mitigates SLD, as reported for chronic marihuana smokers, whereas in obese mice hCB1R tonically inhibit FAO, which promotes SLD and underlies the anti-steatotic effect of peripheral CB1R blockade.

Tuberous sclerosis complex (TSC) promotes renal cyst formation and chronic kidney disease through mechanistic target of rapamycin complex 1 (mTORC1) dysregulation, yet effective treatments remain limited. Using mouse models with Tsc1 deletion in nephron progenitor cells and CRISPR-edited human kidney cells, we assessed the role of the endocannabinoid system in TSC-associated kidney disease. Tsc1 deletion led to significant alterations in endocannabinoid levels and the expression of metabolizing enzymes. These molecular changes were accompanied by receptor dysregulation, characterized by CB1R upregulation and CB2R downregulation in cyst-lining epithelial cells. A similar receptor imbalance was observed in TSC1-deficient human kidney cells, suggesting a conserved pathogenic mechanism. Treatment with the peripheral CB1R antagonist JD5037 significantly reduced mTORC1 activity and c-Myc expression in cultured cells and ex vivo kidney organ cultures. These findings identified CB1R as a potential therapeutic target, linking endocannabinoid dysregulation to TSC kidney pathology.NEW & NOTEWORTHY This study reveals for the first time that TSC-associated kidney disease involves significant dysregulation of the endocannabinoid system in both murine models and human kidneys, characterized by altered endocannabinoid levels, enzyme expression changes, CB1R upregulation, and CB2R downregulation in cyst-lining epithelial cells. Treatment with the peripheral CB1R antagonist effectively suppressed mTORC1 hyperactivation and c-Myc expression, identifying CB1R as a novel therapeutic target for TSC-associated renal pathology.

The development of peripherally selective cannabinoid-1 receptor (CB₁R) antagonists offers a promising strategy for obesity treatment. Here, we evaluated the efficacy of novel tricyclic CB₁R antagonists, focusing on BNS808. Our findings demonstrate that BNS808 exhibits robust CB₁R antagonism with notable CB₂R selectivity, minimal brain penetration, and potent in vitro and in vivo efficacy. The compound's high plasma protein binding reduces free drug availability for CNS entry, enhancing safety and minimizing drug-drug interactions. In diet-induced obese mice, BNS808 effectively reduced body weight, adiposity, liver triglycerides, and liver enzymes, supporting its peripherally mediated action. These results highlight BNS808 as a promising candidate for obesity treatment. Additionally, our novel library of peripherally selective CB₁R antagonists provides a strong foundation for future drug development. With further refinement, BNS808 holds significant clinical potential to address the global obesity epidemic.

Introduction: 

This study aimed to evaluate the utilization of medical cannabis in a pediatric population and compare short-term persistence rates with those in adolescents and young adults.

Methods: 

In this retrospective, nationwide cohort study supplemented by data from an open-label study of children with ASD, patient cases under 12 years of age who received medical cannabis treatment between 2018 and 2022 were analyzed. The primary outcome assessed was treatment persistence within the first 3 months. Secondary outcomes included changes in THC ratios, amounts dispensed, and reasons for treatment discontinuation.

Results: 

The patient population consisted of 1,341 children using medical cannabis for ASD (751), epilepsy (330), Tourette syndrome (165), and pediatric cancer (95). Out of 3,007 consecutive medical cannabis sessions, the adjusted hazard ratio for discontinuation in the first 3 months was 0.83 (95% CI [0.71–0.96], p = 0.01) for young adults compared to children. Approximately 60%–70% of children discontinued therapy within the first 6 months. Significant alterations in THC ratios or dispensed amounts were observed in most sessions within the initial 6 months. In the open-label study dataset, most treatment discontinuations were primarily attributed to adverse effects and a perceived lack of therapeutic efficacy.

Conclusion: 

Our findings suggest that short-term persistence of medical cannabis therapy is lower in children compared to adolescents and young adults. Moreover, many pediatric patients required adjustments to their THC ratios and showed a high frequency of treatment discontinuation. These observations underscore the importance of targeted strategies to improve medical cannabis treatment effectiveness and adherence in the pediatric population. Although MC may offer therapeutic benefits for pediatric patients, our findings emphasize the importance of careful patient selection and close medical follow-up to optimize clinical outcomes.

There is a potential link between cannabis and mental disorders. Cannabis exposure involves in many cases negative mental emotions, which are unpleasant sensations or thoughts. Whereas mild cases of negative mental emotions inflict patient's quality of life, more severe cases lead to therapy discontinuations, or even hospitalizations and death. This study characterizes cannabis users who experienced negative mental emotions after cannabis exposure. The Releaf App database was utilized to evaluate the association between personal and cannabis use characteristics on reporting a negative mental emotion during cannabis exposure. This global mobile lets individuals track real-time cannabis experience use with cannabinoid-based products, containing data points such as gender, age, reasons for use, product type, cannabis composition, and feelings and emotions experienced after cannabis use. Multivariable logistic regression models were constructed, adjusting for potential confounders such as gender and previous experience with cannabis use. The study population comprised 4,435 users, and 34,279 sessions were collected from various countries, mainly from North America, and included in the primary analysis. Reporting on negative mental emotions was associated with users in the age group of 18-30 years. Using cannabis for a mental purpose was associated with a small increase in reporting on negative mental emotions (OR = 1.10, 95%CI [1.03-1.19]). Oral products were associated with reporting on negative mental emotions. THC-dominant products were associated with reporting negative mental emotions compared to balanced products (OR = 1.21, 95%CI [1.06-1.38]). This study suggests that some characteristics of cannabis use, such as young age and oral consumption are associated with negative mental emotions. Further studies should examine the interface between cannabis consumption, characteristics of consumers, and negative emotional experience or even long-term mental disorders.

Gardnerella vaginalis is a natural inhabitant of the vagina, but when an imbalance occurs in the vaginal microbiota, this bacterium can cause vaginosis, a condition that must be treated when symptomatic and prior to a gynecological intervention. Cannabidiol (CBD) is an anti-inflammatory compound that also has antibacterial activities against several Gram-positive and certain Gram-negative bacteria. Objectives: Since G. vaginalis is an opportunistic pathogenic Gram-variable bacterium, we investigated its response to CBD. Methods: The antibacterial activity of CBD was studied by broth dilution assay, changes in intracellular ATP levels, and the ability of bacteria to recover on chocolate agar plates. The antibiofilm activity was investigated by MTT metabolic assay, crystal violet staining, and HR-SEM. Flow cytometric analyses were performed to measure changes in membrane potential, membrane perforation, and metabolic activity. Reactive oxygen species (ROS) production was analyzed using the nitro blue tetrazolium (NBT) reagent. Gene expression was determined by semi-quantitative real-time PCR, while protein composition was determined by LC-MS/MS analysis. Results: We observed that G. vaginalis clinical isolates exhibited high susceptibility to CBD with a minimum inhibitory concentration (MIC) of 2.5 µg/mL CBD. CBD induced rapid membrane hyperpolarization and caused cytoplasmic leakage of ATP without increasing propidium iodide uptake. This was accompanied by reduced metabolic activity and loss of survivability. Proteomic analysis revealed decreased expression of some ribosomal-associated proteins. CBD exhibited antioxidant activity by reducing intracellular ROS levels in a dose-dependent manner. The antibacterial effect was neutralized by the free radical scavenger α-tocopherol, suggesting the involvement of radicals in executing the antibacterial effect. Importantly, CBD not only prevented the biofilm formation of G. vaginalis but also reduced the metabolic activity and biofilm biomass of preformed, mature biofilms. Real-time PCR analysis of G. vaginalis treated with CBD for 6 h showed an increase in the expression of biofilm-associated genes, suggesting that the antibiofilm activity of CBD is mainly due to its antibacterial effect. CBD did not alter the ability of G. vaginalis to adhere to HeLa cervical carcinoma cells and CBD-treated bacteria were still phagocytosed by RAW264.7 macrophages. Conclusions: Our study shows that CBD exhibits antibacterial and antibiofilm activities against G. vaginalis clinical isolates and is thus a potential drug for the treatment of vaginosis caused by this bacterium.

Cannabidiol (CBD) is a natural compound from the Cannabis sativa L. plant, which has anti-inflammatory, anti-nociceptive, neuroprotective, and antibacterial activities. Objective: The aim of this study was to develop a sustained-release device of CBD that can provide an antibacterial effect against the Gram-positive bacteria Streptococcus mutans and Staphylococcus aureus for extended periods of time. Methods: CBD was incorporated into the biodegradable PURASORB 5010 or PURASORB 7510 DL-lactide/glycolide polymers using either dimethylsulfoxide (DMSO) or acetone as the solvent, and the dried polymer scaffolds were exposed daily to a fresh culture of bacteria. The bacterial growth was determined daily by optical density, and the metabolic activity of biofilms was determined using the MTT assay. Biofilm formation on the polymer scaffolds was visualized by HR-SEM. Its anti-inflammatory effect was determined by measuring the IL-6 release from LPS-stimulated RAW 264.7 macrophages by ELISA. Cell cytotoxicity on normal Vero epithelial cells was determined by the MTT assay. The daily release of CBD was determined by gas chromatography–mass spectrometry (GC-MS). Results: PURASORB 5010/CBD scaffolds had antibacterial activity against S. mutans UA159, S. aureus ATCC25923, and a clinical isolate of a multidrug-resistant S. aureus (MDRSA CI-M) strain for the tested period of up to 17 days. PURASORB 7510/CBD scaffolds also had antibacterial activity, but overall, it was less effective than PURASORB 5010/CBD over time. The addition of PEG400 to the copolymers significantly increased the antibacterial activity of PURASORB 7510/CBD but not of PURASORB 5010/CBD. The daily release of CBD from the polymer scaffolds was sufficient to reduce the LPS-induced IL-6 secretion from RAW 264.7 macrophages, and importantly, it was not cytotoxic to either RAW 264.7 macrophages or Vero epithelial cells. The daily release of CBD was found to be between 1.12 and 9.43 µg/mL, which is far below the cytotoxic dose of 25 µg/mL. Conclusions: The incorporation of CBD into the biodegradable PURASORB 5010 can be used to prepare sustained-release devices for medical purposes where combined antibacterial and anti-inflammatory activities are desirable.

The cannabinoid receptor type 1 (CB₁R), a key component of the endocannabinoid system (ECS), has been implicated in various oncogenic processes. Its overexpression in breast cancer has been associated with tumor progression and metastasis, primarily through regulation of the cell cycle. Given its role in cancer biology, CB₁R represents a promising therapeutic target. In this study, we utilized Proteolysis Targeting Chimera (PROTAC) technology to design and synthesize a series of bifunctional small molecules capable of selectively degrading CB₁R in cancer cells. These compounds were specifically engineered to avoid central nervous system (CNS) penetration, thereby minimizing adverse effects linked to the parent compound, Rimonabant. Several of the synthesized molecules effectively induced CB₁R degradation. The most promising lead compound not only reduced CB₁R-associated downstream signaling but also suppressed cancer cell proliferation and promoted apoptosis, highlighting its therapeutic potential. Importantly, in a 3D spheroid cancer model, the lead compound significantly reduced tumor growth compared to the known CB₁R antagonist Rimonabant, demonstrating superior efficacy in targeting both individual cancer cells and complex tumor architecture. Consistent with its design, in vivo evaluation confirmed that the compound does not significantly penetrate the blood–brain barrier, supporting its peripheral selectivity. Overall, our findings establish targeted CB₁R degradation via PROTACs as a viable and innovative strategy for cancer therapy, paving the way for the development of next-generation, precision-targeted therapeutics.

Objective: Aging is associated with reduced central nervous system endocannabinoid tone. Here we ‎sought to decipher the involvement of hypothalamic cannabinoid receptor type-1 (Cnr1) in ‎driving peripheral tissue aging, with a particular focus on bone and joint structural changes.

Methods: To this end, we generated mice with hypothalamus-specific ablation of Cnr1 (i.e., CB1^hypoKO), or with hypothalamus-specific rescue of the receptor (CB1^STOPhypoRS) using stereotaxic viral injections into the mediobasal hypothalamus at 2-3-‎months of age in Cnr1^fl/fl or CB1^STOP mice. Animals were aged to 18 or 19 months and assessed for body weight, ‎temperature, frailty and circulating hormones. After sacrifice, we examined structural and histological features of hypothalamic tissue, skin, ‎testis, joint, and bone as well as circulating hormone levels.

Results: CB1^hypoKO exhibited reduced frailty index vs WT at 17 months of age, with unchanged body weight, temperature and survival. Interestingly, CB1^hypoKO mice displayed a reduction in the lateral meniscal ‎mineral volume of the tibiofemoral joint, which was associated with less blood vessels and articular cartilage damage. Immunofluorescence analysis revealed that CB1^hypoKO mice displayed enriched tyrosine hydroxylase (TH) intensity surrounding blood vessels, yet meniscal tissue showed reduced TH positive cells and ATF4 nuclear co-appearence in CB1^hypoKO mice vs WT. Finally, CB1^hypoKO mice displayed signficantly lower circulating levels of corticosterone.

Conclusions: These results suggest that a lack of hypothalamic CB1 tone reduced circulating levesl of corticosterone, while increasing local meniscal sympathetic tone, which is associated with impaired ATF4 nuclear localization and meniscal mineralization. These events subsequently hinder OA development with age.

Major depressive disorder (MDD) is a leading cause of disability worldwide. Unfortunately, approximately 30 % of MDD patients do not respond to available antidepressants, and characterization of novel molecular mediators of MDD is urgently needed. Chronic stress, a key risk factor for MDD, induces widespread neurobiological changes, including alterations in synaptic plasticity and neurotransmission. However, the molecular mechanisms mediating these effects remain poorly defined. In this study, we provide evidence that Neurensin-2, a stress-inducible vesicular protein, regulates the cannabinoid receptor 1 (CB1R), an important mediator of depression. In N2a cells, overexpression of Neurensin-2 was associated with reduced CB1R expression and attenuation of its downstream signaling; the Akt, mTOR, and Erk1/2 pathways. In these cells, Neurensin-2 co-localized with CB1R and reduced the expression of this receptor in both the membrane and intracellular organelles. The Neurensin-2-CB1R relationship was examined in vivo using the chronic social defeat stress (CSDS) model, where stress exposure was accompanied by increased Nrsn2 and decreased Cnr1 expression in the mouse hippocampus. Notably, stress-induced Cnr1 downregulation was not observed in Neurensin-2 knockout mice, suggesting that Neurensin-2 plays a role in stress-induced downregulation of CB1R in vivo. We further confirmed these expression patterns within the hippocampal inhibitory neuronal population that highly co-expresses Neurensin-2 and CB1R, the CCK-positive hippocampal interneurons. These findings uncover a novel stress-induced pathway that inhibits CB1R signaling by Neurensin-2. Thus, we suggest that Neurensin-2 is a potential therapeutic target for treatment-resistant depression.

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.