Abstract
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 Avy hIAPP 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. 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.
Highlights
Amyloid deposits in pancreatic islets, mainly formed by human islet amyloid polypeptide aggregation, have been associated with loss of β-cell mass and function, and are a pathological hallmark of type 2 diabetes (T2D)
Given that we previously reported that PBA treatment improves glucose metabolism in lean mice overexpressing human islet amyloid polypeptide (hIAPP), in the present study we focused on the effect of PBA in Avy and Avy hIAPP m ice[29]
The present study, we show that oral treatment with the chemical chaperone PBA improves glucose homeostasis and reduces amyloid deposits in a mouse model characterized by obesity and β cell dysfunction due to hIAPP overexpression, highlighting the potential of this drug for the treatment of T2D
Summary
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). PBA treatment strongly reduced the severe hyperglycemia observed in obese Avy hIAPP mice in fasting and fed conditions throughout the study. This effect was paralleled by a decrease in hyperinsulinemia. One of the hallmarks of T2D is the presence of amyloid deposits in pancreatic islets, which are associated with β cell mass reduction[2] These deposits are mainly formed by a β cell-secreted hormone known as islet amyloid polypeptide (IAPP) or amylin. The conversion of a normally soluble protein into amyloid structures underlies the pathogenesis induced by hIAPP aggregation through cell toxicity and cell d eath[6]
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