دورية أكاديمية
Pharmacological potential of novel agonists for FFAR4 on islet and enteroendocrine cell function and glucose homeostasis.
| العنوان: | Pharmacological potential of novel agonists for FFAR4 on islet and enteroendocrine cell function and glucose homeostasis. |
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| المؤلفون: | McCloskey AG; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland., Miskelly MG; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland., Flatt PR; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland., McKillop AM; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland. Electronic address: am.mckillop@ulster.ac.uk. |
| المصدر: | European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2020 Jan 15; Vol. 142, pp. 105104. Date of Electronic Publication: 2019 Oct 25. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Science B.V Country of Publication: Netherlands NLM ID: 9317982 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0720 (Electronic) Linking ISSN: 09280987 NLM ISO Abbreviation: Eur J Pharm Sci Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Amsterdam : Elsevier Science B.V Original Publication: Amsterdam ; New York : Elsevier, c1993- |
| مواضيع طبية MeSH: | Aniline Compounds/*pharmacology , Enteroendocrine Cells/*drug effects , Glucose/*metabolism , Homeostasis/*drug effects , Hypoglycemic Agents/*pharmacology , Insulin-Secreting Cells/*drug effects , Receptors, G-Protein-Coupled/*agonists , Sulfonamides/*pharmacology, Animals ; Blood Glucose/drug effects ; Diabetes Mellitus, Experimental/drug therapy ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/metabolism ; Enteroendocrine Cells/metabolism ; Glucagon-Like Peptide 1/metabolism ; Insulin/metabolism ; Insulin-Secreting Cells/metabolism ; Male ; Mice ; Receptors, G-Protein-Coupled/antagonists & inhibitors |
| مستخلص: | Background: To investigate the metabolic effects of FFAR4-selective agonists on islet and enteroendocrine cell hormone release and the combined therapeutic effectiveness with DPP-IV inhibitors. Methods: Insulinotropic activity and specificity of FFAR4 agonists were determined in clonal pancreatic BRIN-BD11 cells. Expression of FFAR4 was assessed by qPCR and western blotting following agonist treatment in BRIN-BD11 cells and by immunohistochemistry in mouse islets. Acute in-vivo effects of agonists was investigated after intraperitoneal (i.p.) or oral administration in lean and HFF-obese diabetic mice. Results: GSK137647 (10 - 11 -10 - 4 M) and Compound-A (10 - 10 -10 - 4 M) stimulated insulin secretion at 5.6 mM (p < 0.05-p < 0.001) and 16.7 mM (p < 0.05-p < 0.001) glucose in BRIN-BD11 cells, with no cytotoxicity effects as assessed by MTT. FFAR4 antagonist (AH-7614) abolished the insulintropic effect of GSK137647 (p < 0.05-p < 0.001), whilst FFAR1 antagonist (GW1100) had no effect. Incubation of BRIN-BD11 cells with GSK137647 and Compound-A increased FFAR4 (p < 0.01) gene expression at 16.7 mM glucose, with a corresponding increase in FFAR4 (p < 0.01) protein concentrations. FFAR4 upregulation was attenuated under normoglycaemic conditions. Immunohistochemistry demonstrated co-localisation of FFAR4 and insulin in mouse islets. Orally administered GSK137647 or Compound-A (0.1 µmol/kgBW) improved glucose tolerance (p < 0.001), increased plasma insulin (p < 0.001), GLP-1 (p < 0.05), GIP (p < 0.05) and induced satiety (p < 0.001) in HFF mice, with glucose-lowering effects enhanced in combination with DPP-IV inhibitor (Sitagliptin) (p < 0.05). Conclusions: Specific FFAR4 agonism improves glucose tolerance through insulin and incretin secretion, with enhanced DPP-IV inhibition in combination with Sitagliptin. General Significance: These findings have for the first time demonstrated that selective FFAR4 activation regulates both islet and enteroendocrine hormone function with agonist combinational therapy, presenting a promising strategy for the treatment of type-2-diabetes. (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Combinational Therapy; DPP-IV Inhibition; FAR4; Incretin; Insulin; Specificity |
| المشرفين على المادة: | 0 (Aniline Compounds) 0 (Blood Glucose) 0 (FFAR4 protein, mouse) 0 (GSK137647) 0 (Hypoglycemic Agents) 0 (Insulin) 0 (Receptors, G-Protein-Coupled) 0 (Sulfonamides) 89750-14-1 (Glucagon-Like Peptide 1) IY9XDZ35W2 (Glucose) |
| تواريخ الأحداث: | Date Created: 20191101 Date Completed: 20200601 Latest Revision: 20200601 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1016/j.ejps.2019.105104 |
| PMID: | 31669388 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1879-0720 |
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| DOI: | 10.1016/j.ejps.2019.105104 |