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  • Consistent with previous reports of

    2022-01-27

    Consistent with previous reports of an association between increased accumulation of cAMP and GLP-1 secretion [25, 44, 45], we hypothesized that Oleoyl-LPI may regulate GPR119 activation and secretion of GLP-1 secretion through the cAMP/PKA/CREB pathway. Pharmacological inhibition of PKA by H-89 was able to reduce Oleoyl-LPI-induced GLP-1 secretion only slightly. Because the reduction of GLP-1 secretion is not statistically significant (Fig. 5), this indicates that Oleoyl-LPI-mediated activation of CREB is partially dispensable for the secretion of GLP-1 in this system. In addition, our data show that Oleoyl-LPI induced GLP-1 secretion primarily depends on ERK 1/2 activation. Pharmacological blockade of MEK 1/2 with PD98059 significantly inhibited Oleoyl-LPI mediated GLP-1 secretion (Fig. 4C and D), but synergism with PKA appears essential for maximal GPR119 mediated GLP-1 secretion (Supplementary Fig. 4).
    Conclusion This study demonstrated that Oleoyl-LPI is the specific species of LPI that is involved in the regulation of GLP-1 secretion from enteroendocrine L-cells. We have identified a signalling pathway involving GPR119 activation, that signals downstream through both the ERK1/2 and the cAMP/PKA/CREB pathway (Fig. 5). The following are the supplementary data related to this article.
    Conflict of interest
    Transparency document
    Acknowledgements The authors acknowledge the infrastructure and staff support provided by the School of Biomedical Sciences and CHIRI, Faculty of Health Sciences Curtin University. Work in the Falasca lab is supported by Diabetes Australia. S.A.A. received a full SLAI scholarship from Ministry of Higher Learning, Malaysia. S.P. is supported by the Curtin University Health Sciences Faculty International Research Scholarships. We thank Prof David Baker for the GPR55−/− mice.
    The prevalence of type 2 1,3-PBIT dihydrobromide (T2DM; non-insulin dependent diabetes) is increasing worldwide in all age groups. In order to deal with this situation several T2DM drugs have been developed in past few decades, which are included but not limited to, biguanides, sulfonylureas, thiazolidinediones, meglitinides, glucagon-like peptide 1 (GLP-1) analogs, DPP-4 inhibitors, and SGLT-2 inhibitors., , , , One of current focuses on diabetes drug discovery is to identify new agents that protect and preserve pancreatic β-cells. G protein-coupled receptor 119 (GPR119) is activated by endogenous ligand, which in turn, induces glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells and GLP-1 in intestine. GLP-1 has β-cell protection and preservation potential through accumulating intracellular c AMP and enhancing adenylate cyclase activation. Moreover, it also has the ability to improve glucose homeostasis while concurrently slowing gastric emptying by reducing the food intake and promoting weight loss., , All of these characteristics make GPR119 a promising target for the treatment of T2DM. According to recent studies, many GPR119 agonists have been reported, and few GPR119 agonists have been entered into clinical trials but none have been approved up to date. In our recent work, we have also identified a series of thienopyrimidine derivatives. Most GPR119 agonists display structural similarities, featuring a polar moiety (head group) such as methylsulfonyl or tetrazole groups, , , , , , , , (). With the goal of identifying a novel chemotype, we replaced the polar head (methylsulfonyl or tetrazole) with diverse functional groups and identified -alkoxyamide moiety as a methylsulfonyl or tetrazole surrogate. Thus, we report the synthesis and biological evaluation of new -alkoxyamide GPR119 agonists. The general synthetic procedure is outlined in . Commercially available 4-bromobenzoyl chloride was coupled with ,-dimethylhydroxylamine to yield , which was borylated by cross-coupling with bis(pinacolato)diboron to pinacol ester . Borylated compound was coupled with thienopyrimidine or pyridine derivative to obtain products and . Boc groups of compounds and were deprotected by 4M HCl to yield and , which were further substituted with 5-ethylpyrimidyl or isopropyl carboxylate moieties to obtain and .