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

J Pharmacol Sci. 2012;118(1):65-74. doi: 10.1254/jphs.11072fp. Epub 2011 Dec 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Calcium / metabolism
  • Cell Line
  • Cricetinae
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress / drug effects
  • Exenatide
  • 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
  • Venoms / pharmacology*

Substances

  • Hypoglycemic Agents
  • Peptides
  • Venoms
  • Glucagon-Like Peptide 1
  • Exenatide
  • Glyburide
  • Calcium