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    • The following are the supplementary data related to

    2021-11-30

    The following are the supplementary data related to this article.
    Authorship SLC and CGE performed the study conception and experimental design, wrote the paper and directed the activities of this work. ESM and JICA performed most of the degranulation assays, [Ca2+] measurements regarding to the effects of anandamide, HU308 and LPI on BMMCs, some RT-PCRs and contributed to the writing of the article; RDCV performed initial degranulation and [Ca2+] measurements, together with analysis of Fyn KO Torin1 and the effect of AM9810. AIS generated all BMMCs needed for the study, performed the RT-PCR for cytokine mRNA analysis and immunoprecipitation experiments, and contributed to the discussion of the results.
    Introduction Type 2 Diabetes Mellitus (T2DM) is characterised by chronic hyperglycaemia, and insulin resistance and β-cell dysfunction are the main defects in T2DM. β-cell dysfunction leads to a defect in insulin secretion, which is the key process in the progression of T2DM. It has been suggested that β-cell dysfunction is the critical determinant in the progression of T2DM [1], so preserving β-cell function and mass is an important therapeutic target for the treatment of T2DM [[2], [3], [4]]. Endoplasmic reticulum (ER) stress is one of the main causes of β-cell apoptosis and dysfunction in T2DM [[5], [6], [7]]. In normal conditions, glucose stimulates a 20-fold increase in insulin biosynthesis [8], however during chronic hyperglycaemia, the high demand of insulin biosynthesis overwhelms the ER folding capacity, which causes an overload of misfolded proteins in the ER lumen, thus leading to ER stress [9,10]. Therefore, it has been suggested that ameliorating ER stress could prevent from β-cell apoptosis and treat T2DM [[11], [12], [13]]. G-protein coupled receptor 55 (GPR55) is an orphan G-protein coupled receptor, which is activated by some certain endocannabinoids and lipid transmitters. Recently, GPR55 was shown to play a role in the regulation of glucose and energy homeostasis [[14], [15], [16]]. Besides, GPR55 agonism was able to increase glucose-induced insulin secretion in isolated human and mouse islets of Langerhans, and clonal beta BRIN-BD11 cells [[16], [17], [18], [19]]. Interestingly, O-1602, a GPR55 agonist, increased insulin secretion in islets from wild-type mice, but not in GPR55 knockout mice [16,19], and O-1602 injection improved glucose tolerance in mice [16]. Furthermore, a recent study showed that GPR55 knockout mice displayed impaired insulin sensitivity in peripheral metabolic tissues, and GPR55 agonists could enhance insulin sensitivity in cultured skeletal muscle cells, hepatocytes and adipocytes [20]. Taken together, this suggested a role of GPR55 in glucose homeostasis and insulin sensitivity. GPR55 was shown to play a role in glucose homeostasis and insulin sensitivity, however its role in ER stress-induced β-cell apoptosis was never studied. Therefore in the present study, we investigated the effect of potent synthetic GPR55 agonists, O-1602 and abnormal cannabidiol (Abn-CBD), on ER stress-induced apoptosis in mouse pancreatic β-cell lines, MIN6 and Beta-TC-6, and its underlying mechanisms. Our results showed that O-1602 and Abn-CBD protected from ER stress-induced apoptosis through the activation of 3′-5′-cyclic adenosine monophosphate response element-binding protein (CREB), thus up-regulating anti-apoptotic genes, Bcl-2 and Bcl-xL. In addition, O-1602 and Abn-CBD directly activated 3 kinases, CaMKIV, Erk1/2 and PKA, to induce CREB activation. Taken together, our study provided a novel effect of GPR55 agonists on ER stress-induced β-cell apoptosis, and our study together with other studies suggested that GPR55 could be a potential target for treating T2DM [[15], [16], [17],20,21].
    Materials and methods
    Results
    Discussion Preserving β-cell function and mass is an important therapeutic target for the treatment of T2DM [[2], [3], [4]]. GPR55 was shown to play a role in glucose and energy homeostasis, and insulin sensitivity [[14], [15], [16],19,20], however its role in ER stress-induced β-cell apoptosis was never studied. Therefore, the present study investigated the novel effect of O-1602 and Abn-CBD on ER stress-induced apoptosis in MIN6 and Beta-TC-6 cells. Here, we were the first to demonstrate that GPR55 agonists, O-1602 and Abn-CBD, could protect β-cells against ER stress-induced apoptosis. Interestingly, the protective effect was through the activation of CREB, hence up-regulating anti-apoptotic genes, Bcl-2 and Bcl-xL. Besides, O-1602 and Abn-CBD could directly activate 3 kinases, CaMKIV, PKA and Erk1/2, to induce CREB activation. Taken together, this study suggested a protective role of GPR55 agonists against ER stress-induced β-cell apoptosis, and provided novel mechanisms underlying this protection.