A new synthetic dual agonist of GPR120/GPR40 induces GLP-1 secretion and improves glucose homeostasis in mice.

G-protein coupled receptors 40 and 120 (GPR40 and GPR120) are increasingly emerging as potential therapeutic targets for the treatment of altered glucose homeostasis, and their agonists are under evaluation for their glucagon-like peptide-1 (GLP-1)-mediated therapeutic effects on insulin production and sensitivity. Here, we characterized a new dual GPR40 and GPR120 agonist (DFL23916) and demonstrated that it can induce GLP-1 secretion and improve glucose homeostasis. Resulting from a rational drug design approach aimed at identifying new dual GPR120/40 agonists able to delay receptor internalization, DFL23916 had a good activity and a very high selectivity towards human GPR120 (long and short isoforms) and GPR40, as well as towards their mouse orthologous, by which it induced both Gαq/11-initiated signal transduction pathways with subsequent Ca intracellular spikes and G protein-independent signaling via β-arrestin with the same activity. Compared to the endogenous ligand alpha-linolenic acid (ALA), a selective GPR120 agonist (TUG-891) and a well-known dual GPR40 and GPR120 agonist (GW9508), DFL23916 was the most effective in inducing GLP-1 secretion in human and murine enteroendocrine cells, and this could be due to the delayed internalization of the receptor (up to 3 h) that we observed after treatment with DFL23916. With a good pharmacokinetic/ADME profile, DFL23916 significantly increased GLP-1 portal vein levels in healthy mice, demonstrating that it can efficiently induce GLP-1 secretion in vivo. Contrary to the selective GPR120 agonist (TUG-891), DFL23916 significantly improved also glucose homeostasis in mice undergoing an oral glucose tolerance test (OGTT).