Fig. 1. Tirzepatide stimulates insulin secretion in mice predominantly through the GLP-1R.
a, Mouse islets from control mice and mice with beta-cell-specific deletion of the Gipr (Gipr-β-cell-/-) were perifused with ramping concentrations of tirzepatide (TZP) (0–100 nM) with or without Ex9 at a 1 μM concentration beginning at minute 28. The iAUC was calculated for TZP using the value at minute 42 as the baseline. n = 5 for all groups. b, Mouse islets were perifused with increasing concentrations of TZP (0–100 nM) in the presence of Ex9, a GIPR antagonist (GIPR ant) or a combination of both. All antagonists were used at 1 μM concentrations starting at minute 28. The iAUC was calculated for TZP using the value at minute 42 as the baseline. PBS and GIPR ant, n = 4; Ex9 and Ex9 + GIPR ant, n = 5. c, Glycemia after a 5 h fast, immediately before the administration of glucose. Antagonists were administered 2 h before and TZP was administered 1 h before. n = 8 for all groups. d, Glycemia during the IPGTT. The iAUC was calculated using the fasting glycemia value. PBS, TZP and TZP + GIPR ant, n = 8; TZP + GLP-1R ant and TZP + GLP-1R/GIPR ant, n = 7. All values are mean ± s.e.m. Statistical tests were two-way ANOVA with Tukey’s post-hoc test (a) and one-way ANOVA with Tukey’s post-hoc test (b–d).