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Correction published on 9 May 2020, see Int. J. Mol. Sci. 2020, 21(9), 3357.
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Article

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

by
Noura Al-Zamel
1,
Suleiman Al-Sabah
1,*,
Yunus Luqmani
2,
Lobna Adi
1,
Siby Chacko
1,
Tom Dario Schneider
3 and
Cornelius Krasel
4
1
Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, PO Box 24923, 13110 Safat, Kuwait
2
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, PO Box 24923, 13110 Safat, Kuwait
3
Institute of Forensic Medicine, Department of Forensic Pharmacology and Toxicology, University of Zurich, 190/52 CH-8057 Zurich, Switzerland
4
School of Pharmacy, Institute for Pharmacology and Toxicology, The Philipps University of Marburg, Karl-von-Frisch-Straße, 135033 Marburg, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(14), 3532; https://doi.org/10.3390/ijms20143532
Submission received: 13 June 2019 / Revised: 6 July 2019 / Accepted: 12 July 2019 / Published: 19 July 2019
(This article belongs to the Special Issue The Biology and Pharmacology of Glucagon)
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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: GLP-1; GIP; glucagon; receptor; arrestin GLP-1; GIP; glucagon; receptor; arrestin

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MDPI and ACS Style

Al-Zamel, N.; Al-Sabah, S.; Luqmani, Y.; Adi, L.; Chacko, S.; Schneider, T.D.; Krasel, C. 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, 20, 3532. https://doi.org/10.3390/ijms20143532

AMA Style

Al-Zamel N, Al-Sabah S, Luqmani Y, Adi L, Chacko S, Schneider TD, Krasel C. 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. International Journal of Molecular Sciences. 2019; 20(14):3532. https://doi.org/10.3390/ijms20143532

Chicago/Turabian Style

Al-Zamel, Noura, Suleiman Al-Sabah, Yunus Luqmani, Lobna Adi, Siby Chacko, Tom Dario Schneider, and Cornelius Krasel. 2019. "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" International Journal of Molecular Sciences 20, no. 14: 3532. https://doi.org/10.3390/ijms20143532

APA Style

Al-Zamel, N., Al-Sabah, S., Luqmani, Y., Adi, L., Chacko, S., Schneider, T. D., & Krasel, C. (2019). 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. International Journal of Molecular Sciences, 20(14), 3532. https://doi.org/10.3390/ijms20143532

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