Exendin-4 Protects Against Sulfonylurea-Induced β-Cell Apoptosis

• Published in: Journal of Pharmacological Sciences Vol. 118; no. 1; pp. 65 - 74
• Main 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
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 2012; The Japanese Pharmacological Society; Elsevier
• Subjects: Animals; apoptosis; Apoptosis - drug effects; Calcium - metabolism; Cell Line; Cricetinae; endoplasmic reticulum (ER) calcium depletion; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress - drug effects; ER stress; Exenatide; glucagon like peptide-1(GLP-1); Glucagon-Like Peptide 1 - agonists; Glyburide - adverse effects; Hypoglycemic Agents - adverse effects; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Peptides - pharmacology; Rats; Rats, Sprague-Dawley; sulfonylurea; Venoms - pharmacology; ER stress; endoplasmic reticulum (ER) calcium depletion; sulfonylurea; apoptosis; glucagon like peptide-1(GLP-1)
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.11072FP

Sulfonylurea is one of the commonly used anti-diabetic drugs that stimulate insulin secretion from β-cells. Despite their glucose lowering effects in type 2 diabetes mellitus, long-term treatment brought on secondary failure characterized by β-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 β-cells after the induction of oxidative and ER stress. In this study, we examined the antiapoptotic action of a GLP-1 analogue in β-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 glibenclamide-induced β-cell loss and therapeutic availability of GLP-1–based drugs in secondary failure by sulfonylurea during treatment of diabetes.