TZ-GLP-2

Mayendraraj A, Rosenkilde MM, Gasbjerg LS

Peptides

A review of class B1 G-protein-coupled receptor pharmacology at the glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) in pancreatic beta cells, characterizing their individual and shared downstream cyclic-AMP signaling pathways and describing how a dual GIPR/GLP-1R agonist exhibits biased signaling at the GLP-1 receptor alongside potent GIP-receptor engagement.

Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al.

JCI insight

In cell-based receptor assays and isolated mouse pancreatic islets, this dual GIP/GLP-1 receptor agonist mimicked native GIP signaling at the GIP receptor, while at the GLP-1 receptor it showed biased signaling favoring cyclic-AMP generation over beta-arrestin recruitment and reduced receptor internalization relative to native GLP-1; islet experiments indicated beta-arrestin-1 constrains the insulin-secretory response to GLP-1 but not to GIP or the dual agonist, consistent with a receptor-selective imbalanced-agonism mechanism.

Yuliantie E, Darbalaei S, Dai A, Zhao P, Yang D, Sexton PM, et al.

Biochemical pharmacology

In HEK293 cells recombinantly expressing human GIP receptor or GLP-1 receptor, this dual GIPR/GLP-1R agonist showed a signaling bias toward ERK1/2 phosphorylation relative to cyclic-AMP accumulation at both receptors compared with the native GIP and GLP-1 ligands, distinguishing its receptor-pathway selectivity from mono-agonist and endogenous incretin comparators tested in the same cell system.

Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al.

JCI Insight

This receptor-pharmacology study quantified the compound’s occupancy and signaling at the GIP and GLP-1 receptors, showing greater engagement of the GIP receptor and, at the GLP-1 receptor, a signaling bias toward cAMP generation over beta-arrestin recruitment with weaker receptor internalization; in primary mouse islets, beta-arrestin1 limited the GLP-1 (but not GIP or the dual agonist) insulin response, characterizing an imbalanced, biased dual-agonist mechanism.