title: Exendin-4 protects against sulfonylurea-induced β-cell apoptosis.
abstract: 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 Ca(2+) 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 anti-apoptotic 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 Ca(2+)-ATPase (SERCA) 2/3 was determined by real-time PCR and western blot analysis. Chronic exposure to glibenclamide increased apoptosis by depletion of ER Ca(2+) concentration through reduced expression of SERCA 2/3. Pretreatment with Exendin-4 had an anti-apoptotic role through ER stress modulation and ER Ca(2+) 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.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Konyang University School of Medicine, Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Dong-Mee
authors.initials: DM
authors.lastname: Lim
authors.forename: Hyung-Seo
authors.initials: HS
authors.lastname: Park
authors.forename: Chan-Il
authors.initials: CI
authors.lastname: Moon
authors.forename: Kyung-Jin
authors.initials: KJ
authors.lastname: Choi
authors.forename: Seong-Kyu
authors.initials: SK
authors.lastname: Lee
authors.forename: Haing-Woon
authors.initials: HW
authors.lastname: Baik
authors.forename: Keun-Young
authors.initials: KY
authors.lastname: Park
authors.forename: Byung-Joon
authors.initials: BJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000819:agonists*; D005905:Glyburide / Q000009:adverse effects; D007004:Hypoglycemic Agents / Q000009:adverse effects; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014688:Venoms / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D005905:Glyburide; D002118:Calcium