Protective Effects of Glucagon Like Peptide-1 on HIT-T15 β Cell Apoptosis via ER Stress Induced by 2-deoxy-D-glucose

Abstract

Background: The characteristic feature of pancreatic β cells is highly developed endoplasmic reticulum (ER) due to a heavy engagement in insulin secretion. The ER serves several important function, including post-translational modification, folding, and assembly of newly synthesized secretory proteins, and its proper function is essential to cell survival. Various stress conditions can interfere with ER function. Pancreatic β cells may be particularly vulnerable to ER stress that causes to impair insulin biosynthesis and β cell survival through apoptosis. Glucagon like peptide-1 (GLP-1) is a new drug for treatment of type 2 diabetes and has effects on stimulation of insulin secretion and β cell preservation. Also, it may have an antiapoptotic effect on β cells, but detailed mechanisms are not proven. Therefore, we investigated the protective mechanism of GLP-1 in β cells through ER stress response induced by 2-deoxy-D-glucose (2DG). Methods: For induction of the ER stress, HIT-T15 cells (hamster β cell line) were treated with 2DG (10 mM). Apoptosis was evaluated with MTT assay, hoechst 33342 staining and Annexin/PI flow cytometry. Expression of ER stress-related molecules was determined by real-time PCR or western blot. For blocking ER stress, we pretreated HIT-T15 cells with exendin-4 (Ex-4; GLP-1 receptor agonist) for 1 hour before stress induction. Results: After induction with ER stress (2DG), β cells were lost by apoptosis. We found that Ex-4 had a protective effect through ER stress related molecules (GRP78, GRP94, XBP-1, eIF2α, CHOP) modulation. Also, Ex-4 recovered the expression of insulin2 mRNA in β cells. Conclusion: These results suggest that GLP-1 may protect β cells apoptosis through ER stress modulation. (KOREAN DIABETES J 32:477-487, 2008)