Exendin-4 protects against sulfonylurea-induced β-cell apoptosis

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 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 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. © the japanese pharmacological society.