A Dual GLP-1/GIP Receptor Agonist Does Not Antagonize Glucagon at Its Receptor but May Act as a Biased Agonist at the GLP-1 Receptor

Int J Mol Sci. 2019 Jul 19;20(14):3532. doi: 10.3390/ijms20143532.

Abstract

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important regulators of metabolism, making their receptors (GLP-1R and GIPR) attractive targets in the treatment of type 2 diabetes mellitus (T2DM). GLP-1R agonists are used clinically to treat T2DM but the use of GIPR agonists remains controversial. Recent studies suggest that simultaneous activation of GLP-1R and GIPR with a single peptide provides superior glycemic control with fewer adverse effects than activation of GLP-1R alone. We investigated the signaling properties of a recently reported dual-incretin receptor agonist (P18). GLP-1R, GIPR, and the closely related glucagon receptor (GCGR) were expressed in HEK-293 cells. Activation of adenylate cyclase via Gαs was monitored using a luciferase-linked reporter gene (CRE-Luc) assay. Arrestin recruitment was monitored using a bioluminescence resonance energy transfer (BRET) assay. GLP-1, GIP, and glucagon displayed exquisite selectivity for their receptors in the CRE-Luc assay. P18 activated GLP-1R with similar potency to GLP-1 and GIPR with higher potency than GIP. Interestingly, P18 was less effective than GLP-1 at recruiting arrestin to GLP-1R and was inactive at GCGR. These data suggest that P18 can act as both a dual-incretin receptor agonist, and as a G protein-biased agonist at GLP-1R.

Keywords: GIP; GLP-1; arrestin; glucagon; receptor.

MeSH terms

  • Amino Acid Sequence
  • Arrestin / metabolism
  • Arrestin / pharmacology
  • Bioluminescence Resonance Energy Transfer Techniques
  • Dose-Response Relationship, Drug
  • Glucagon / metabolism*
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Glucagon-Like Peptide-1 Receptor / metabolism*
  • HEK293 Cells
  • Humans
  • Ligands
  • Peptides / chemistry
  • Peptides / pharmacology
  • Receptors, Gastrointestinal Hormone / agonists*
  • Receptors, Gastrointestinal Hormone / metabolism*
  • Receptors, Glucagon / antagonists & inhibitors
  • Receptors, Glucagon / metabolism*

Substances

  • Arrestin
  • Glucagon-Like Peptide-1 Receptor
  • Ligands
  • Peptides
  • Receptors, Gastrointestinal Hormone
  • Receptors, Glucagon
  • Glucagon
  • gastric inhibitory polypeptide receptor