Incretins play an important role in FFA4/GPR120 regulation of glucose metabolism by GW-9508

Aine M McKillop, Michael G Miskelly, Brian M Moran, Peter R Flatt

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Abstract

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.

Original languageEnglish
Article number121475
Pages (from-to)1-10
Number of pages10
JournalLife Sciences
Volume318
Early online date7 Feb 2023
DOIs
Publication statusPublished (in print/issue) - 1 Apr 2023

Bibliographical note

Funding Information:
These studies were supported by the Department of Education and Learning, Northern Ireland . The authors thank Prof DJ Drucker (Toronto, Canada) for providing GLUTag cells/GLP-1R KO mice; Prof B Thorens, (Lausanne, Switzerland) for the GIPR KO mice and Dr. B. Wice (Washington University of St. Louis) for pGIP/neo STC-1 cells.

Publisher Copyright:
© 2023

Keywords

  • G-protein couples receptor
  • GW-9508
  • GIP
  • GLP-1
  • Glucose
  • Diabetes
  • G-protein coupled receptor

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