Insulin and Incretin Receptor Agonists Reciprocally Alter Their Blood–Brain Barrier Permeabilities

Figures

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  Figure 1. Effect of acute brain insulin receptor inhibition on 125I-dulaglutide (BAF) BBB pharmacokinetics. Delta 125I-dulaglutide (BAF) pharmacokinetics were measured for (A) whole brain (n = 9–11) and (B) olfactory bulb (n = 7–12) 10 min after a 1 µL ICV injection of vehicle or S961 (1 µg). Males (triangles) and females (circles) were combined for the linear regression (Vehicle—solid line, S961—dotted line).

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  Figure 2. Effect of IV insulin co-administration on 125I-dulaglutide (BAF) BBB pharmacokinetics. Delta 125I-dulaglutide (BAF) pharmacokinetics were measured in male and female mice combined for multiple brain regions in the presence or absence of co-administered IV insulin (1 µg). Linear regressions for each region within each group were calculated, and the resulting slope (Ki) is presented. Full linear regression data and sample size are listed in Table 2. “Too variable” indicates that the linear regression data was too variable and not significant. * p < 0.05, *** p < 0.001.

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  Figure 3. Effect of IV dulaglutide (BAF) co-administration on 125I-insulin BBB pharmacokinetics. Delta 125I-insulin pharmacokinetics were measured for (A) whole brain (n = 12) and (B) olfactory bulb (n = 11–12) in the presence or absence of co-administered IV dulaglutide (BAF) (1 µg). Males (triangles) and females (circles) were combined for the linear regression (Vehicle—solid line, Dulaglutide (BAF)—dotted line). Veh: vehicle, Dula: dulaglutide (BAF).

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  Figure 4. Metabolic effects of chronic semaglutide treatment. Male and female lean mice were treated for two weeks with s.c. semaglutide (dose escalation to 10 nmol/kg). (A,B) Body weights (n = 19 male, n = 20 female) and (C,D) food intake (n = 5 cages male, n = 3 cages female) were measured each injection day. Fasting (E) blood glucose (n = 11 male Veh, n = 13 female Veh, n = 13 male Sema, n = 13 female Sema), (F) insulin (n = 9 male Veh, n = 11 female Veh, n = 8 male Sema, n = 10 female Sema), (G) leptin (n = 9 male Veh, n = 11 female Veh, n = 9 male Sema, n = 10 female Sema), and (H) GLP-1 (n = 6 male Veh, n = 7 female Veh, n = 5 male Sema, n = 6 female Sema) were measured in a subset of mice from the three combined cohorts at the end of the treatment period (n = 11 male Veh, n = 13 male Sema, n = 13 female Veh, n = 13 female Sema). Two-way ANOVA with Fisher’s uncorrected LSD post hoc test: * p < 0.05, *** p < 0.001, ns = not significant, p < 0.10. Grey bars = vehicle treated, white bars = semaglutide treated. Veh: vehicle, Sema: semaglutide.

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  Figure 5. Effect of chronic semaglutide treatment on IV 125I-insulin BBB pharmacokinetics. Delta 125I-insulin BBB pharmacokinetics were measured for (A,B) whole brain (n = 5–6) and (C,D) olfactory bulb (n = 5) in male and female mice following two weeks of s.c. semaglutide (dose escalation 1–10 nmol/kg) treatment. * p < 0.05 between slopes (Ki).

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  Figure 6. Effect of semaglutide treatment on in situ 125I-insulin BBB pharmacokinetics. Delta 125I-insulin pharmacokinetics were measured in the absence of blood (in situ) for (A,B) whole brain (n = 7–8) and (C,D) olfactory bulb (n = 7) in male and female mice following two weeks of s.c. semaglutide (dose escalation up to 10 nmol/kg) treatment. * p < 0.05 between slopes (Ki). Veh: vehicle, Sema: semaglutide.