A GLP-1 receptor agonist attenuates human islet amyloid polypeptide-induced autophagy and apoptosis in MIN6 cells

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by the dysfunction and loss of pancreatic islet β-cells, in part due to islet amyloid deposits derived from islet amyloid polypeptide (IAPP). The glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 enhances the insulin secretory response by increasing β-cell mass in T2DM. However, it is unknown whether exendin-4 protects β-cells from IAPP-mediated autophagy and apoptosis. In the present study, reverse transcription-quantitative polymerase chain reaction, ELISA and western blotting were used to detected the mRNA and protein expression of insulin/hIAPP and other signaling molecules, while the mechanisms underlying these effects were also determined. Exendin-4 increased the level of insulin secretion, which was greater than that of IAPP, leading to a beneficial IAPP/insulin secretion pattern. In MIN6 cells incubated with 25 mM glucose, exendin-4 decreased the ratio of light chain 3 (LC3)-II/I, which was accompanied by an increase in p62 protein. In a hIAPP-overexpressing MIN6 cell model, exendin-4 prevented the hIAPP-induced increase in the LC3II/I ratio and decrease in p62 expression. In addition, exendin-4 pretreatment reduced hIAPP-induced activation of cleaved caspase-3, suggesting that exendin-4 may protect MIN6 cells against apoptosis. Taken together, the results highlight hIAPP as a critical mediator of β-cell loss and suggest that the GLP-1 receptor agonist exendin-4 may be a potential therapeutic agent for hIAPP-induced β-cell damage.