The endocannabinoid system was originally described to be involved in the psychotropic effects of cannabis. However, accumulating evidence underscores its role in modulating metabolism and energy homeostasis as well as modulating key processes involved in the pathophysiology of diabetes-related inflammation and apoptosis. Downstream signalling is triggered through the cannabinoid receptors CB1R and GPR55 present on beta cells and responsible for beta cell function and proliferation, and CB2R, mainly present in immune cells and beta cells, regulating their activation.
Targeting cannabinoid receptors in pancreatic beta cells
Drugs targeting these receptors improve autoimmune diseases such as multiple sclerosis, Crohn’s disease and rheumatoid arthritis, while pharmacological blockade of CB1R was even used in clinical practice to treat complicated obesity. Of note, chronic low-grade inflammation is emerging as an important factor in type 2 diabetes (T2D) pathogenesis. In vivo experiments in an animal model of prediabetes helped identify inflammation as an important cellular process being modulated by cannabinoid drugs. The key objective of the DIRECtA project, which was undertaken with the support of the Marie Skłodowska-Curie (MSC) programme and that of national and regional funding agencies, was to study the impact of targeting cannabinoid receptors (CBRs) on insulitis and the onset of type 1 diabetes (T1D). “We hypothesised that the use of drugs targeting CBRs could be a powerful treatment to prevent insulitis, preserve beta cells and stop progression towards loss of endogenous insulin production,” explains Francisco Javier Bermúdez-Silva, team leader at the host lab. Researchers used a combination of CBR pharmacological and genetic targeting strategies to decipher the potential benefits of cannabinoids in T1D. They treated transgenic mice lacking CB1R only in pancreatic beta cells, non-obese diabetic (NOD) mice and healthy mice with synthetic cannabinoids and analysed the outcome. Overall, they discovered that blockade of CB1R or activation of CB2R or GPR55 reduces intra-islet inflammation and delays insulitis progression and T1D onset.
Project significance and future directions
Currently there are no strategies to prevent or cure T1D, and patients require exogenous insulin injections for life. Existing treatments aim to reduce T-cell reactivity at early disease stages when islets are still not destroyed. Immunosuppression fails to show durable effects and has a detrimental impact on the patient’s immune system. “The novelty of DIRECtA lies in exploring the potential of cannabinoid drugs to prevent/avoid insulitis during autoimmune attack in diabetes,” emphasises the MSC fellow Isabel González-Mariscal. The proposed approach aims to modulate the own beta cell’s reactivity and not simply focus on the immune system alone. The fellow actively takes part in related research and has contributed to a number of publications on the topic. Although cannabinoid drugs have been administered to obese patients, improving key parameters such as triglycerides, HDL cholesterol and insulin resistance, side effects and lack of knowledge on their mode of action have led to their withdrawal from the market. DIRECtA provided important mechanistic insight into the role of the endocannabinoid system in insulitis and T1D development, a step towards opening up the market to cannabinoid drugs. Researchers are currently analysing the status of the endocannabinoid system in white blood cells from people with recent onset of T1D, as well as assessing the ability of cannabinoids to counteract insulitis in isolated human islets from healthy donors. Collectively, project activities will support the exploration of this strategy in clinical trials to assess the efficacy and safety of cannabinoid-targeting compounds for preventing T1D.
DIRECtA, insulitis, T1D, cannabinoid drugs, diabetes, pancreatic beta cells, endocannabinoid, cannabinoid receptor, inflammation, T2D