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.

Mechanisms of Beta-Cell Apoptosis in Type 2 Diabetes-Prone Situations and Potential Protection by GLP-1-Based Therapies

“…Only a limited number of studies have investigated the potential impact of GLP-1RA on IAPP toxicity. Exendin-4 alleviated h-IAPP-induced apoptosis in MIN6 [ 191 ] and in INS-1E [ 192 ] beta-cell lines, in islets from h-IAPP transgenic mice [ 193 ] or in human islets [ 194 , 195 ]. The protection was not associated with a reduced formation of h-IAPP deposits [ 192 ], but with increased levels of AKT phosphorylation [ 192 , 193 , 194 , 195 ].…”

“…A reduced JNK activation has not always been noticed [ 192 , 195 ], and exendin-4 protection from h-IAPP toxicity does not seem to alleviate ER stress in INS-1E cells [ 192 ]. Finally, an improvement of the autophagic flux by exendin-4 was reported in MIN6 cells overexpressing h-IAPP [ 191 ].…”

Identification of key candidate genes and pathways revealing the protective effect of liraglutide on diabetic cardiac muscle by integrated bioinformatics analysis

“…Liraglutide is a glucagon-like peptide-1 (GLP-1) analog that binds to the GLP-1R receptor and has been shown to be abundantly expressed by RGC-5 cells (4). A GLP-1 homolog, exendin , is 53% similar in sequence homology and is commonly utilized as a GLP-1 receptor antagonist in experimental studies (5). Zhang et al reported Glp1r expression on retinal ganglion cells and investigated the GLP-1 protective mechanisms against hyperglycaemic conditions (6).…”

Research Progress on Relationship between Iron Metabolism and Type 2 Diabetes and Intervention Effect of GLP-1

“…Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by glucose and lipid metabolism disorders, which are mainly characterized by decreased number, hypofunction and increased apoptosis of pancreatic β-cells. It has been shown that the mechanisms involved in the development of T2DM caused by multidimensional pathogenic responses in pancreatic β-cells include pathological processes such as cell iron death, endoplasmic reticulum (ER) stress, reactive oxygen species activation, membrane disruption, and receptor-mediated signaling impairment transduction cascades [1]. Iron metabolism plays an important role in the development and progression of a variety of metabolic diseases, especially T2DM.The first case to investigate the relationship between iron metabolism and diabetes is hereditary hemochromatosis (HH), and the specific mechanism of HH-associated diabetes pathogenesis remains incompletely clarified, and insulin deficiency and insulin resistance (IR) may be important contributing factors.…”