Tirzepatide (LY3298176) Acetate (2023788-19-2 free base) is a new molecule that can control blood glucose levels by combining dual agonism of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors.[3]

METHODS: Tirzepatide (LY3298176) (1, 3, 10, 30 nM) was used to treat GIPR or GLP-1R receptors, and Tirzepatide (30 μM, 30 nM) was used to treat cells expressing recombinant GIPR or GLP-1R to investigate whether it is effective on both GIPR and GLP-1R.
RESULTS In receptor binding studies, LY3298176 had high affinity to either receptor (GIPR Ki = 0.135, SEM = 0.020 nM; GLP-1R Ki = 4.23, SEM = 0.23 nM); for GIPR, the affinity was comparable to that of native GIP, while for GLP-1R, the affinity was approximately 5-fold weaker than that of native GLP-1. In signaling studies using the same HER2 receptors, LY3298176 potently stimulated cAMP accumulation at either receptor (GIPR EC50 = 0.0224, SEM = 0.0053 nM; GLP-1R EC50 = 0.934, SEM = 0.068 nM).[1]
METHODS: Representative confocal images of Tirzepatide (LY3298176)-induced receptor internalization and EGFP fluorescence in HA-GIPR-EGFP cells treated with Tirzepatide (LY3298176) (100 nM).
RESULTS Tirzepatide (LY3298176) was weak in inducing internalization, resulting in a maximal effect of only 40% of that observed with GLP-1. Treatment with Tirzepatide (LY3298176) resulted in minimal reduction in cell surface labeling and only a slight increase in punctate localization of the receptor in the cytoplasmic/perinuclear region. [2]

METHODS: Tirzepatide (LY3298176) (30nmol/kg，i.p) was used to evaluate in vivo glycemic control using an intraperitoneal glucose tolerance test (ipGTT) in normal and receptor-deficient mice.
RESULTS Tirzepatide (LY3298176) enhanced insulin secretion in three pancreatic islet genotypes. Tirzepatide (LY3298176) can induce glucose-dependent insulin secretion in vivo through GIPR or GLP-1R and improve glucose tolerance in mice. [1]