Chemical chaperone-conjugated exendin-4 as a cytoprotective agent for pancreatic β-cells
- Authors
- Son, S.; Park, E.J.; Kim, Y.; Lee, K.C.; Na, D.H.
- Issue Date
- Dec-2018
- Publisher
- Elsevier Ltd
- Keywords
- Chemical chaperone; Diabetes; Exendin-4; Endoplasmic reticulum stress; Tauroursodeoxycholic acid
- Citation
- International Journal of Biochemistry and Cell Biology, v.105, pp 13 - 19
- Pages
- 7
- Journal Title
- International Journal of Biochemistry and Cell Biology
- Volume
- 105
- Start Page
- 13
- End Page
- 19
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/3451
- DOI
- 10.1016/j.biocel.2018.09.018
- ISSN
- 1357-2725
1878-5875
- Abstract
- Endoplasmic reticulum stress has been considered a major cause of pancreatic β-cell dysfunction and apoptosis leading to diabetes. Glucagon-like peptide-1 receptor activation and chemical chaperones have been known to reduce endoplasmic reticulum stress and improve β-cell function and survival. The purpose of this study was to prepare and evaluate the chemical chaperone tauroursodeoxycholic acid-conjugated exendin-4 as a protective agent for pancreatic β-cells. Mono-tauroursodeoxycholic acid-Lys27-exendin-4 conjugate (TUM1-Ex4) showed better receptor binding affinity than other conjugates with strong in vitro insulinotropic activity in rat pancreatic β-cells and in vivo hypoglycemic activity in type 2 diabetic db/db mice. In INS-1 cells under endoplasmic reticulum stress induced by thapsigargin, TUM1-Ex4 promoted cell survival in a dose-dependent manner. In western blot analysis, TUM1-Ex4 reduced the expression of the endoplasmic reticulum stress marker GRP78 and phosphorylation of the translation initiation factor eIF2α. These results reveal that TUM1-Ex4 accelerates translational recovery and contributes to β-cell protection and survival. The present study indicates that the chemical chaperone-coupled glucagon-like peptide-1 receptor agonist is a feasible therapeutic strategy to enhance β-cell function and survival. © 2018 Elsevier Ltd
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