Type I Diabetes Vaccine And Cannabinoid Receptors Are Used As Targets For Type 2 Diabetes Drugs

Background and Aim:The endocannabinoid signalling(ECS)system has been known to regulate glucose homeostasis.Previous studies have suggested that the cannabinoid 2(CB2)receptor may play a regulatory role on insulin secretion,immune modulation and insulin resistance.Given that diabetes and insulin resistance are attributable to elevated inflammatory tone,we investigated the role of CB2 receptor on glucose tolerance and insulin sensitivity in high fat diet(HFD)/streptozotocin(STZ)-induced mice.Type 1 diabetes(T1D)is an autoimmune disease caused by autoreactive T cells that react against insulin-producing islet β cells.Insulin replacement is currently used as the main therapeutic option for T1D patients,although it could not correct immunological disruption which is fundamental to the onset of T1D.We use autologous antigens to investigate aiming to restore autoimmunity,preserve β cells and insulin secretory responses in T1D individuals.Methods:Diabetes was induced in male ICR mice by HFD/STZ and exposed to a CB2 receptor agonist,SER601,for 2-or 4-weeks via subcutaneous implantation of osmotic minipumps.Glucose and insulin tolerance tests were performed at the end of treatment.Islets were isolated for assessment of β cell function.Pancreases and skeletal muscles were also obtained for histological analyses.In the study of T1D,we used peptide Ins B9-23(preproinsulin Ⅱ33-47),a well-known insulin epitope that is recognised by T cells and thus critical to the initiation of autoimmune response to insulin.Mannosylated sodium alginate microparticals(1μm in diameter)or PLGA microparticals were used as delivery vehicle to target endogenous dendritic cells and facilitate antigen presentation to induce immune tolerance in vivo.Results:Despite a lack of impact on glucose tolerance,substantial improvement on insulin sensitivity was observed in SER601-treated mice,which could partly be attributed to improved islet β-cell function,shown as increased glucose-induced insulin secretion and insulin content.No changes on islet macrophage infiltration or skeletal muscle fat deposition were detectable from SER601-treated mice.However,a major decrease in body weight was recorded at the end of 4-week SER601 exposure,accompanied by a lack of epididymal adipose mass in SER601-treated mice.Treatment of PLGA encasulated peptide Ins B9-23 microparticals enhanced expression of IL-10 in Serum of NOD Mice.As a results,It can effectively prevent NOD mice form the onset of of type 1 diabetic and improve the survival rate.Conclusion:Our data suggest a lipolytic role of SER601 in HFD/STZ-induced diabetic mice,which results in significant improvement of systemic insulin sensitivity.Thus,the CB2 receptor may be considered a promising target for therapeutic development against insulin resistance and obesity-related diabetes.Treatment of PLGA encasulated peptide Ins B9-23 microparticals can effectively prevent NOD mice form the onset of type 1 diabetic and improve the survival rate.