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  • br GPR GPR has been described as a

    2021-10-16


    GPR55 GPR55 has been described as a type 3 cannabinoid receptor due to its ability to detect endocannabinoids and may play a role in the endocannabinoid lipid sensing system [28]. GPR55 is activated by both cannabinoid endogenous agoinsts (endocannabinoids) and non-cannabinoids fatty acids namely L-α-lysophatidylinositol (LPI) [29]. GPR55 was found on islet β-cells and a range of GPR55 agonists were identified as potent mediators of insulin release in vitro and in vivo [29]. Activation of GPR55 results in coupling to Gα12/13 and Gαq proteins enhancing intracellular Ca2+, PLC, extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and Rho kinase [29, 30]. Interestingly, a recent study found that GPR55 has an integral role in energy homeostasis with decreased insulin sensitivity, physical activity and increased adiposity [31].
    GPR119 GPR119 is expressed in the pancreas, intestines and regions of the central nervous system, with distribution on islet β-cells, α-cells and PP cells [32, 33]. In the intestines, GPR119 is located on the enteroendocrine L- and K-cells and is involved in the secretion of GLP-1 and GIP []. GPR119 is activated by fatty cannabinoid receptors ethanolamides and results in coupling to Gαs with stimulation of the adenylate cyclase pathway, leading to cAMP and PKA generation [3•, 32]. GPR119 synthetic agonist AS-1269574 has been shown to stimulate GLP-1 secretion via TRPA1 cation channels []. Synthetic agonists for GPR119 exhibited anti-hyperglycaemic and insulinotropic in animal models but have had limited potency in clinical trials in humans to date [35].
    Emerging GPCR therapies The ideal GPCR would exhibit high expression on insulin secreting β-cells, GLP-1 secreting L-cells, GIP producing K-cells with effects on CNS inducing satiety and decreasing food intake. A future therapeutic approach may include utilising synthetic incretin secretagogues to stimulate endogenous GLP-1 and GIP from L- and K-cells in addition to DPP-4 inhibitors [36]. Currently, only incretin based therapies are clinically available for the treatment of type 2 diabetes including GLP-1 receptor agonists (Exenatide, Liraglutide Exenatide-LAR, Lixisenatide, Dulaglutide) and DPP-4 inhibitors (Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin) [5•, 37, 38•]. Data from animal studies indicate that biologically stable forms of CCK, OXM and GIP may have therapeutic potential in the future []. Indeed, some incretin mimetics such as Liraglutide have been approved for anti-obesity actions by the FDA in 2014 [39, 40, 41]. Incretin based therapies have been associated with an increased risk of pancreatitis, which could lead to pancreatic adenocarcinoma [41]. A recent population based study found that the use of cannabinoid receptors incretin based therapies was not linked to an increased risk of pancreatic cancer compared to sulphonylureas [42]. Another approach that is currently under investigation is the development of dual acting agonists (GLP-1-GIP, GLP-1-Glucagon (GCG)) or more recently triple acting agonists (GLP-1-GIP-GCG) [43, 44, 45••, 46•, 47••, 48, 49•]. Several pre-clinical and clinical trials are currently ongoing in double acting agonists including Cpd86 (Lilly) a GLP-1/GIP dual agonist (pre-clinical), ZP2929 (Zealand Pharma) a GLP-1/GCG dual agonist (phase I) and MAR709 (Roche) a GLP-1/GIP dual agonist (phase II) []. Administration of peptides are usually by subcutaneous injection while there are only a few oral peptides available including TTP273/TTP054 (TransTech Parma) a GLP-1 analogue undergoing phase II clinical trial []. GPR40 agonist, TAK-875 (Takeda) has undergone phase I and II clinical trials with promising anti-diabetic properties, however in December 2013 the phase III clinical trial was terminated due to concerns regarding hepatotoxicity [51]. The exact mechanism of TAK-875 induced liver toxicity remains to be elucidated, however TAK-875 may affect bilirubin and bile acid homeostasis increasing bilirubin concentrations and cholestatic hepatotoxicity [52]. Numerous GPR40 ligands are currently being investigated for the treatment of type 2 diabetes in pre-clinical trials and clinical trials including JTT-851 (Japan Tobacco- phase II), P11187 (Piramal- phase I), AMG-837 (Amgen-phase I) and LY2881835 (Eli Lilly-phase I) [51]. GPR119 agonists GSK-1292263 (GlaxoSmithKline), SAR-26003/MBX-2982 (Sanofi-Aventis/Metabolex) and PSN-821 (Astellas/Prosidion) have all completed stage II clinical trials showing promising anti-diabetic properties [53]. Recently, a GPR120 agonist, KDT501 (KinDex Pharmaceuticals) has entered phase II clinical trials for controlling blood glucose, insulin regulation and pro-inflammatory signals in subjects with insulin resistance [54].