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  • However Gingrich and Hen reported that absence of

    2021-09-14

    However, Gingrich and Hen reported that absence of the gene at all stages of ontogenesis of mice may interfere with the normal developmental program and/or the organism may undergo changes in other systems to compensate for gene absence (46). In addition, potentially altered maternal behavior of GPR40/FFAR1 KO dams might have a great impact on the resulting phenotype of adult KO offspring because of significant role of maternal behavior in the expression of a phenotype change in adult mice (47), (48). Therefore, we cannot excluded that obtained behavioral and physiological changes can be attributed to above-mentioned factors.
    Conflict of interest
    Acknowledgments This study was supported by 1) Grants-in-Aid and Special Coordination Funds from the Kobe Gakuin University Joint Research (A), 2) the Takeda Pharmaceutical Sciences and 3) a Grants-in-Aid for Scientific Research (C) (15K10566) from the Ministry of Education, Culture, Sports, Science and Technology, Japan and the Takeda Science Foundation.
    Type II diabetes is characterized by an inability to maintain glucose homeostasis due to insulin desensitization and/or insufficient insulin secretion. GPR40, also known as free fatty Amfenac Sodium Monohydrate receptor 1 (FFAR1), is a member of the G-protein-coupled lipid-activated family of receptors and is primarily expressed in pancreatic beta cells and intestinal enteroendocrine cells, and to a lesser extent the brain. When activated by its endogenous ligands (medium and long chain fatty acids) GPR40 elicits increased insulin secretion from islet β-cells only in the presence of elevated glucose levels. This unique mechanism to treat type II diabetes has the potential to mitigate the risk of hypoglycemia seen with other insulin secretagogues and has triggered significant efforts at identifying therapeutic agents utilizing this target. Clinical candidates targeting GPR40 as a means to treat diabetes have been reported in the literature, , , and have been solely represented by orthosteric agonists such as TAK-875 () that partially activate the receptor. This direct binding to the orthosteric domain has been shown to have provided clinical proof of concept for the mechanism by lowering HbA1c through GPR40-mediated insulin secretion. TAK-875, the most clinically advanced GPR40 partial orthosteric agonist, was terminated in Phase III due to concerns about liver toxicity. Lipophilic carboxylic acid such as TAK-875 readily form acyl glucuronides in vivo, which may give rise to reactive metabolites that contribute toward the observed DILI signal., Recently, a different approach to the utilization of GPR40 mediated insulin secretion as a therapeutic target had been initially reported by researchers at Amgen, , and Bristol-Myers-Squibb wherein they described GPR40 full agonists whose mode of action is via positive allosteric modulation (effectively AgoPAMs), on orthosteric ligands (e.g. DHA). Further evidence of the proposed mode of action of AgoPAMs was recently disclosed where we showed cooperative allostery of AgoPAMs by simultaneously co-crystallizing a full orthosteric agonist and an AgoPAM within the GPR40 receptor. In addition to stimulating insulin secretion via pancreatic action, GPR40 AgoPAMs are known to stimulate GLP-1 secretion in the gut, potentially accounting for the observed enhancement in efficacy. Moreover, we have recently reported the discovery of a novel class of biaryl chromans, i.e. compound , that operate as selective GPR40 AgoPAMs which demonstrated superior on-target in-vivo glucose lowering efficacy over GPR40 partial orthosteric agonists TAK-875 with no sign of tachyphylaxis in a 2-week in-vivo study.
    Introduction 2-Lysophosphatidylcholines (1-acyl-glycero-3-phosphocholines, 2-LPCs, LPCs), which maintain the acyl chain in sn-1 position, are the most abundant lysophospholipid in nature (D'Arrigo and Servi, 2010). Lipidomic analysis has revealed a correlation of lower plasma concentrations of LPCs with impaired glucose tolerance and obesity (Zhao et al., 2010, Barber et al., 2012). LPC 16∶0 is the most abundant species in human plasma (146 ± 37 μM) followed by LPC 18∶0 (56.5 ± 14.9 μM) and LPC 18∶1 (28.4 ± 12.5 μM) (Heimerl et al., 2014). Although the presence of LPCs in plasma was observed at the beginning of the twentieth century (Kihara et al., 2015), the original observation from Metz's laboratory on dose-dependent lysophospholipid-induced insulin secretion was shown already in 1986 (Metz, 1986) while the involvement of G protein coupled receptor for the effect of LPC on insulin secretion was identified as GPR119 in 2005 (Soga et al., 2005). GPR119 is preferentially expressed on β-cells of the islets of Langerhans but its expression has also been demonstrated in intestinal L- and K-cells, where its activation was associated with secretion of glucagon-like peptide 1 and glucose-dependent insulinotropic peptide (Overton et al., 2006, Sakamoto et al., 2006, Ahlkvist et al., 2013). GPR119 has been shown to bind a variety of lipid-derived ligands, as well as a range of small synthetic molecules. Recent literature data indicate that lysophospholipids also have the ability to interact with other pancreatic receptors regulating carbohydrate metabolism. GPR55 activated by lysophosphatidylinositols may be another attractive target in type 2 diabetes mellitus (T2DM) (Liu et al., 2016). Treatment of diabetic rats with lysophoshatidylinositol has been found to counteract the symptoms of diabetes such as high blood glucose, lower body weight, increase amplitude of slow wave in stomach smooth muscle, and to improve gastric emptying (Lin et al., 2014). Both GPR119 and GPR55 receptors are stimulated by endocannabinoids such as palmitoylethanolamide (PEA), oleoylethanolamide (OEA), arachidonoylethanolamide (anandamide, AEA), and 2-arachidonoylglycerol (2-AG) (Godlewski et al., 2009). We have recently proved that ligand specificity of GPR55 is much wider and our studies evidence that GPR55 is activated also by LPC (Drzazga et al., 2017). However, GPR40 (also known as the free fatty acid receptor 1 or FFAR1) is the best-studied of the cell-surface receptors on β-cells. GPR40 is the most potently activated by endogenous free fatty acids (FFAs) with medium and long (C12-C22) aliphatic chains, resulting in amplification of insulin secretion only in the presence of elevated glucose levels (Itoh et al., 2003, Itoh and Hinuma, 2005, Briscoe et al., 2003). The glucose dependency of insulin secretion makes this receptor an excellent target for developing efficacious therapies with a desired safety profile for use in the treatment of T2DM.