دورية أكاديمية
Incretins play an important role in FFA4/GPR120 regulation of glucose metabolism by GW-9508.
| العنوان: | Incretins play an important role in FFA4/GPR120 regulation of glucose metabolism by GW-9508. |
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| المؤلفون: | McKillop AM; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA, Northern Ireland, UK. Electronic address: am.mckillop@ulster.ac.uk., Miskelly MG; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA, Northern Ireland, UK., Moran BM; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA, Northern Ireland, UK., Flatt PR; School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA, Northern Ireland, UK. |
| المصدر: | Life sciences [Life Sci] 2023 Apr 01; Vol. 318, pp. 121475. Date of Electronic Publication: 2023 Feb 07. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 0375521 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0631 (Electronic) Linking ISSN: 00243205 NLM ISO Abbreviation: Life Sci Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: <2008->: Amsterdam : Elsevier Original Publication: Oxford; Elmsford, N. Y. [etc.] Pergamon Press. |
| مواضيع طبية MeSH: | Diabetes Mellitus, Experimental*/drug therapy , Insulins*/therapeutic use, Mice ; Animals ; Incretins/therapeutic use ; Gastric Inhibitory Polypeptide ; Glucagon-Like Peptide 1/metabolism ; Glucose ; Mice, Knockout ; Blood Glucose/metabolism ; Insulin/metabolism |
| مستخلص: | Aims: To assess the role of GPR120 in glucose metabolism and incretin regulation from enteroendocrine L- and K-cells with determination of the cellular localisation of GPR120 in intestinal tissue and clonal Glucagon-Like Peptide-1 (GLP-1)/Gastric Inhibitory Polypeptide (GIP) cell lines. Main Methods: Anti-hyperglycaemic, insulinotropic and incretin secreting properties of the GPR120 agonist, GW-9508 were explored in combination with oral and intraperitoneal glucose tolerance tests (GTT) in lean, diabetic and incretin receptor knockout mice. Cellular localisation of GPR120 was assessed by double immunofluorescence. Key Findings: Compared to intraperitoneal injection, oral administration of GW-9508 (0.1 μmol/kg body weight) together with glucose reduced the glycaemic excursion by 22-31 % (p < 0.05-p < 0.01) and enhanced glucose-induced insulin release by 30 % (p < 0.01) in normal mice. In high fat fed diabetic mice, orally administered GW-9508 lowered plasma glucose by 17-27 % (p < 0.05-p < 0.01) and augmented insulin release by 22-39 % (p < 0.05-p < 0.001). GW-9508 had no effect on the responses of GLP-1 receptor knockout mice and GIP receptor knockout mice. Consistent with this, oral GW-9508 increased circulating total GLP-1 release by 39-44 % (p < 0.01) and total GIP by 37-47 % (p < 0.01-p < 0.001) after 15 and 30 min in lean NIH Swiss mice. Immunocytochemistry demonstrated GPR120 expression on mouse enteroendocrine L- and K-cells, GLUTag cells and pGIP/Neo STC-1 cells. Significance: GPR120 is expressed on intestinal L- and K-cells and stimulates GLP-1/GIP secretory pathways involved in mediating enhanced insulin secretion and improved glucose tolerance, following oral GW-9508. These novel data strongly support the development of potent and selective GPR120 agonists as an effective therapeutic approach for diabetes. Competing Interests: Declaration of competing interest The authors declare that there no conflicts of interest. (Copyright © 2023. Published by Elsevier Inc.) |
| فهرسة مساهمة: | Keywords: Diabetes; G-protein coupled receptor; GIP; GLP-1; GW-9508; Glucose |
| المشرفين على المادة: | 0 (Incretins) 59392-49-3 (Gastric Inhibitory Polypeptide) 89750-14-1 (Glucagon-Like Peptide 1) IY9XDZ35W2 (Glucose) 0 (Insulins) 0 (Blood Glucose) 0 (Insulin) |
| تواريخ الأحداث: | Date Created: 20230208 Date Completed: 20230307 Latest Revision: 20230307 |
| رمز التحديث: | 20230307 |
| DOI: | 10.1016/j.lfs.2023.121475 |
| PMID: | 36754346 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1879-0631 |
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| DOI: | 10.1016/j.lfs.2023.121475 |