Background: Proinflammatory cytokines are one of the causes of diabetes mellitus. However, the exact molecular mechanism by which proinflammatory cytokines induce β-cell death remains to be clearly elucidated. Glucagon-like peptide-1 (GLP-1) affects the stimulation of insulin secretion and the preservation of β-cells. Additionally, it may exert an antiapoptotic effect on β cells; however, the mechanism underlying this effect has yet to be demonstrated. Therefore, we investigated the protective effects of GLP-1 in endo-plasmic reticulum (ER)-mediated β-cell apoptosis using proinflammatory cytokines. Methods: To induce ER stress, hamster insulin-secreting tumor (HIT)-T15 cells were treated using a mixture of cytokines. Apoptosis was evaluated via MTT assay, Hoechst 33342 staining, and annexin/propidium iodide (PI) flow cytometry. The mRNA and protein expression levels of ER stress-related molecules were determined via PCR and Western blotting, respectively. Nitric oxide was mea-sured with Griess reagent. The levels of inducible nitric oxide synthase (iNOS) mRNA and protein were analyzed via real-time PCR and Western blot, respectively. iNOS protein degradation was evaluated via immunoprecipitation. We pretreated HIT-T15 cells with exendin (Ex)-4 for 1 hour prior to the induction of stress. Results: We determined that Ex-4 exerted a protective effect through nitric oxide and the modulation of ER stress-related molecules (glucose-regulated protein [GRP]78, GRP94, and CCAAT/enhancer-binding protein homologous protein [CHOP]) and that Ex-4 stimulates iNOS protein degradation via the ubiquitination pathway. Additionally, Ex-4 also induced the recovery of insulin2 mRNA expression in β cells. Conclusion: The results of this study indicate that GLP-1 may protect β cells against apoptosis through the ubiquitination pathway. (Endocrinol Metab 26:142-149, 2011)