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.

Noura Al-Zamel,Tom Dario Schneider,Cornelius Krasel,Lobna Adi,Siby Chacko,Suleiman Al-Sabah,Yunus Luqmani

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.

Highlights

Introduction(GLP-1) are peptide hormones secreted from the gut in response to feeding and act to lower postprandial glycaemia by potentiating glucose-induced insulin secretion [1,2]
The incretins, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) are peptide hormones secreted from the gut in response to feeding and act to lower postprandial glycaemia by potentiating glucose-induced insulin secretion [1,2]
GLP-1R, GIPR and the glucagon receptor were labelled at the C-terminus with super yellow fluorescent protein 2 (SYFP2) [37] and generated by amplifying the open reading frame of human GLP-1R, GIPR and GCGR with primers which added a HindIII restriction site ahead of the start codon and replaced the stop codon with an XbaI site

Summary

Introduction

(GLP-1) are peptide hormones secreted from the gut in response to feeding and act to lower postprandial glycaemia by potentiating glucose-induced insulin secretion [1,2]. Their receptors (GIPR and GLP-1R, respectively) are expressed on pancreatic β-cells as well as other cell types, conferring various extra-pancreatic actions to these hormones [3]. An impairment of action of the incretin hormones has been identified as an early and specific characteristic of type-2 diabetes mellitus (T2DM) and is likely to be due to a loss of response to the incretin hormones at the pancreatic β-cell [6].

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