The in vitro effects of Cannabidiol on high glucose levels with miRNA profiling

Abstract

Background: Diabetes is a group of metabolic disorders caused by defects in insulin action, insulin secretion, or both. Diabetes mellitus (DM) is characterised by a chronic hyperglycaemic state. The International Diabetes Federation (IDF) estimated that 456 million adults presented with diabetes in 2017. It is projected that there will be 693 million cases of diabetes by 2045. Oxidative stress plays a role in the pathogenesis of DM, and further research must be conducted to identify therapeutic initiatives to combat oxidative stress to prevent the onset and progression of DM. One of the most consumed drugs worldwide is Cannabis, which is consumed by an estimated 200-300 million people. Research has shown that cannabis may possess antioxidant properties. Cannabis contains more than 545 known compounds and 86 cannabinoid chemicals. The main psychoactive chemical is tetrahydrocannabinol (THC), other cannabinoid chemicals include cannabidiol (CBD) and cannabinol (CBN). Due to the growing burden on the South African health care system, finding innovative ways to treat or prevent DM will be very helpful. The aim of this study is to investigate the biochemical effects of CBD in high glucose conditions in an in vitro liver model. Methodology: Cells were exposed to high glucose (40 mM), low (1 μM) CBD concentration and high (5 μM) CBD concentrations, and a combination of glucose and CBD concentrations for 48 and 72 hours. Quantitative real-time PCR was used to measure oxidative stress genes, including PPARG, SOD, NRF2, NF-κB, HIF1A, GPX, and CAT, as well as miRNA-34a expression. Multiplex assays were used to measure the concentration of inflammatory cytokines, including of IL-6, IL-9, IL-10 and PDGF-BB. Results: Our results demonstrate significant downregulation of CAT, SOD, and Nrf2 genes in response to glucose. At 72 hours, CBD upregulated SOD and reversed glucose-induced downregulation of CAT, suggesting an opposing effect of CBD on glucose-induced oxidative stress. Additionally, CBD modulated the expression of PPARG, HIF-1α, NF-κB, and miRNA-34a, with differential effects depending on exposure duration and concentration. Inflammatory cytokines IL-6, IL-8, and IL-9 exhibited varied responses to glucose and CBD, indicating that CBD may modulate the immune response, with higher doses generally exerting a protective or regulatory effect. PDGF-BB levels were reduced by CBD at 48 hours but increased at 72 hours, suggesting CBD's potential role in cellular repair processes over time. Conclusion: These findings highlight CBD's capacity to counteract some of the detrimental effects of hyperglycaemia, although further research is needed to optimize dosing and fully elucidate the underlying mechanisms.