Amyloid deposits in pancreatic islets, mainly formed by human islet amyloid polypeptide (hIAPP) aggregation, have been associated with loss of β-cell mass and function, and are a pathological hallmark of type 2 diabetes (T2D). Treatment with chaperones has been associated with a decrease in endoplasmic reticulum stress leading to improved glucose metabolism. The aim of this work was to investigate whether the chemical chaperone 4-phenylbutyrate (PBA) prevents glucose metabolism abnormalities and amyloid deposition in obese agouti viable yellow (Avy) mice that overexpress hIAPP in β cells (Avy hIAPP mice), which exhibit overt diabetes. Oral PBA treatment started at 8 weeks of age, when AvyhIAPP mice already presented fasting hyperglycemia, glucose intolerance, and impaired insulin secretion. PBA treatment strongly reduced the severe hyperglycemia observed in obese Avy hIAPP mice in fasting and fed conditions throughout the study.
Fig: Glycemia evolution, glucose and insulin tolerance, and insulin response of AvyhIAPP mice. (A) Fed glycemia and (B) 5-h fasting glycemia were evaluated in wt, hIAPP, Avy and Avy hIAPP mice between 4 and 18 weeks of age. (C) Glucose tolerance tests (2 g/kg glucose) in 8-week-old mice. Glycemia values and the respective areas under the curve (AUC) are shown. (D) Insulin tolerance tests (0.75 U/kg insulin) in 8-week-old mice. Percentages of glycemia values respect to the initial value are represented. (E) Plasma insulin levels just before and 15 min after glucose injection. Results are presented as mean ± SEM of (A,B) 7–34 determinations/group/time point, or (C,D) 12–20 and (E) 8–12 mice/group. Statistical analyses were performed using two-way ANOVA followed by Tukey’s post hoc tests: *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. In A and B, multiple global comparisons considering all the time points in each experimental group were performed. Statistical analysis at specific time points of the insulin tolerance test was performed by two-way ANOVA followed by Tukey’s post hoc tests: #P < 0.05, ###P < 0.001 (Avy vs. wt); *P < 0.05, **P < 0.01 (Avy hIAPP vs. wt).
This effect was paralleled by a decrease in hyperinsulinemia. Importantly, PBA treatment reduced the prevalence and the severity of islet amyloid deposition in Avy hIAPP mice. Collectively, these results show that PBA treatment elicits a marked reduction of hyperglycemia and reduces amyloid deposits in obese and diabetic mice, highlighting the potential of chaperones for T2D treatment.
de Pablo, S., Rodríguez-Comas, J., Díaz-Catalán, D. et al. 4-Phenylbutyrate (PBA) treatment reduces hyperglycemia and islet amyloid in a mouse model of type 2 diabetes and obesity. Sci Rep 11,11878 (2021). https://doi.org/10.1038/s41598-021-91311-2