Fig 1.
Effects of acute GIPR antagonism on glucose homeostasis and insulin secretion.
GIPA-1 and GIPA-2 are antagonists of mouse GIPR. Plots (A and B) shows the inhibition of mouse GIPR by GIPA-1 (A) and GIPA-2(B) in CHO-K1 cells. IC50 values (μM) are indicated on the plots. (C-J) Acute effects of GIPA-1 and GIPA-2 on glucose homeostasis and insulin secretion in lean mice. Oral glucose tolerance tests (C and E), the corresponding areas under the curve (AUC) (D and F) and insulin responses (I) following subcutaneous injections of vehicle, 1,5 and 10 mg/kg GIPA-1 (C and D) or vehicle, 1,5 and 10 mg/kg GIPA-2 (E and F) before an oral glucose administration (1.5 g/kg). (G, H and J) Acute effect of GIPA-2 alone or in combination with mouse GIP on glucose homeostasis and insulin secretion in lean mice. Intraperitoneal glucose tolerance test cute IPGTT (G), the corresponding AUC (H) and insulin response (J) following subcutaneous injections of vehicle, 0.1 mg/kg mouse GIP, 5mg/kg GIPA-2, and combination of both. Group sizes are n = 8, and data are represented as mean ± SEM. Statistical analysis was calculated using two-way ANOVA with Tukey’s post-hoc test (C, E, G and J) and one-way ANOVA with Dunnett’s post-hoc test (D, F, H, I). *: p< 0.05, **: p < 0.01, ***: p < 0.001, ****: p<0.0001 compared to vehicle.
Fig 2.
Effects of chronic GIPR antagonism on body weight, food intake, and fasting blood glucose and insulin.
(A) GIPA-1 and GIPA-2 chronic studies schematic. (B-K) Effects of chronic administration of GIPA-1 and GIPA-2 on body weight (B and C), food intake (D and E), fasting plasma glucose (F and G), fasting plasma insulin (H and I) and HOMA-IR (J and K) in DIO mice. Group sizes are n = 10, and data are represented as mean ± SEM. Statistical analysis was calculated using two-way ANOVA with Tukey’s post-hoc test and one-way ANOVA for AUC with Dunnett’s post-hoc test. *: p< 0.05, **: p < 0.01, ***: p < 0.001, ****: p<0.0001 compared to vehicle.
Fig 3.
Effects of GIPA-1 and GIPA-2 on oral glucose tolerance and insulin responses in DIO mice.
Oral glucose tolerance test (A), the corresponding glucose AUC (B) and insulin responses at 0 min (C) and 30 min (D) after the glucose bolus, following administration of vehicle, 0.2 mg/kg liraglutide, ~4.5 mg/kg GIPA-1 and combination of both for 21 days in DIO mice.(E-H) Effects on oral glucose tolerance test (E and F) on day 17, and insulin tolerance test (G and H) on day study 24, following chronic administration of vehicle, 0.2 mg/kg liraglutide, 10 mg/kg GIPA-2 and combination of both in DIO mice. Group sizes are n = 10, and data are represented as mean ± SEM. Statistical analysis was calculated using two-way ANOVA with Tukey’s post-hoc test and one-way ANOVA with Dunnett’s post-hoc test. *: p< 0.05, **: p < 0.01, ***: p < 0.001, ****: p<0.0001 compared to vehicle.
Fig 4.
The effect of GIPR antagonism alone or in combination with liraglutide on lipid homeostasis in DIO mice.
Effects of GIPA-1 and GIPA-2 on plasma TG (A and B), FFAs (C and D), TC (E and F), epididymal fat weight (G and H) and mesenteric fat weight (I and J) following administration of vehicle, liraglutide, GIPR antagonist, and liraglutide in combination with the GIPR antagonist for 28 days in DIO mice. Group sizes are n = 10, and data are represented as mean ± SEM. Statistical analysis was calculated using one-way ANOVA with Dunnett’s post-hoc test. *: p< 0.05, **: p < 0.01, ***: p < 0.001, ****: p<0.0001 compared to vehicle.