Exendin-4 Protects Against Sulfonylurea-Induced beta-Cell Apoptosis
- Authors
- Kim, Ju-Young; Lim, Dong-Mee; Park, Hyung-Seo; Moon, Chan-Il; Choi, Kyung-Jin; Lee, Seong-Kyu; Baik, Haing-Woon; Park, Keun-Young; Kim, Byung-Joon
- Issue Date
- Jan-2012
- Publisher
- JAPANESE PHARMACOLOGICAL SOC
- Keywords
- endoplasmic reticulum (ER) calcium depletion; apoptosis; ER stress; glucagon like peptide-1(GLP-1); sulfonylurea
- Citation
- JOURNAL OF PHARMACOLOGICAL SCIENCES, v.118, no.1, pp.65 - 74
- Journal Title
- JOURNAL OF PHARMACOLOGICAL SCIENCES
- Volume
- 118
- Number
- 1
- Start Page
- 65
- End Page
- 74
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/16663
- DOI
- 10.1254/jphs.11072FP
- ISSN
- 1347-8613
- Abstract
- Sulfonylurea is one of the commonly used anti-diabetic drugs that stimulate insulin secretion from beta-cells. Despite their glucose lowering effects in type 2 diabetes mellitus, long-term treatment brought on secondary failure characterized by beta-cell exhaustion and apoptosis. ER stress induced by Ca2+ depletion in endoplasmic reticulum (ER) is speculated be one of the causes of secondary failure, but it remains unclear. Glucagon like peptide-1 (GLP-1) has anti-apoptotic effects in beta-cells after the induction of oxidative and ER stress. In this study, we examined the antiapoptotic action of a GLP-1 analogue in beta-cell lines and islets against ER stress induced by chronic treatment of sulfonylurea. HIT-T15 and dispersed islet cells were exposed to glibenclamide for 48 h, and apoptosis was evaluated using Annexin/PI flow cytometry. Expression of the ER stress related molecules and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) 2/3 was determined by real-time PCR and western blot analysis. Chronic exposure to glibenclamide increased apoptosis by depletion of ER Ca2+ concentration through reduced expression of SERCA 2/3. Pretreatment with Exendin-4 had an anti-apoptotic role through ER stress modulation and ER Ca2+ replenishing by SERCA restoration. These findings will further the understanding of one cause of gliben-clamide-induced-beta-cell loss and therapeutic availability of GLP-1 based drugs in secondary failure by sulfonylurea during treatment of diabetes.
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