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Review
. 2023 Sep 5;35(9):1519-1529.
doi: 10.1016/j.cmet.2023.07.010. Epub 2023 Aug 16.

GIPR/GLP-1R dual agonist therapies for diabetes and weight loss-chemistry, physiology, and clinical applications

Jonathan E Campbell  1 , Timo D Müller  2 , Brian Finan  3 , Richard D DiMarchi  4 , Matthias H Tschöp  5 , David A D'Alessio  6
Affiliations
Review

GIPR/GLP-1R dual agonist therapies for diabetes and weight loss-chemistry, physiology, and clinical applications

Jonathan E Campbell et al. Cell Metab. .

Abstract

The incretin system is an essential metabolic axis that regulates postprandial metabolism. The two incretin peptides that enable this effect are the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide 1 (GLP-1), which have cognate receptors (GIPR and GLP-1R) on islet β cells as well as in other tissues. Pharmacologic engagement of the GLP-1R is a proven strategy for treating hyperglycemia in diabetes and reducing body weight. Tirzepatide is the first monomeric peptide with dual activity at both incretin receptors now available for clinical use, and in clinical trials it has shown unprecedented effects to reduce blood glucose and body weight. Here, we discuss the foundational science that led to the development of monomeric multi-incretin receptor agonists, culminating in the development of tirzepatide. We also look to the future of this field and comment on how the concept of multi-receptor agonists will continue to progress for the treatment of metabolic disease.

Keywords: GIP; GLP-1; diabetes; incretin; obesity; tirzepatide.

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Conflict of interest statement

Declaration of interests J.E.C. and D.A.D. receive funding to carry out basic research from Eli Lilly, Novo Nordisk, and Merck MSD. J.E.C. has served in an advisory role for Boehringer Ingelheim and Structure Therapeutics. D.A.D. has served in an advisory role for Structure Therapeutics and Eli Lilly.

Figures

Figure 1.
Figure 1.. Timeline of the discovery of seminal incretin-based therapies.
The left side indicates the year each therapy was approved by the United States Food and Drug Administration (FDA). The right side indicates the year the first communication was published.
Figure 2.
Figure 2.. Tirzepatide action in islet endocrine cells.
Tirzepatide stimulates insulin secretion through both the GLP-1R and GIPR in beta-cells. It engages the GIPR receptor similar to native GIP, acting as a full agonist to signal through both Gs/cAMP and β-arrestin (βarr) pathways. On the other hand, tirzpetide engages the GLP-1R in a biased manner, favoring Gs/cAMP signaling over β-arrestin. Tirzpeatide also stimulates glucagon secretion from alpha-cells through the GIPR through undefined mechanisms.
Figure 3.
Figure 3.. Amino acid sequence of human GIP, GLP-1, glucagon (GCG), NNC0090–2746, and tirzepatide (TZP).
Amino acids are colored according to their specificity for GIP (red), GLP-1 (blue), or glucagon (orange). Amino acids common to all three peptides are shown in gray, while amino acids shared between two peptides are shown with split colors. Aib (green) is a non-proteinogenic amino, while the c-terminal extension of exendin-4 (CEX) is shown in yellow.
Figure 4.
Figure 4.. Key metabolic sites of action for GLP-1 (blue) and GIP (red).
See this image and copyright information in PMC

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