Dipeptidyl peptidase-4 inhibitor, vildagliptin, inhibits pancreatic beta cell apoptosis in association with its effects suppressing endoplasmic reticulum stress in db/db mice

Aims. Vildagliptin promotes beta cell survival by inhibiting cell apoptosis. It has been suggested that chronic ER (endoplasmic reticulum) stress triggers beta cell apoptosis. The objective of the study is to explore whether the pro-survival effect of vildagliptin is associated with attenuation of endoplasmic reticulum stress in islets of db/db mice. Methods. Vildagliptin was orally administered to db/db mice for 6 weeks, followed by evaluation of beta cell apoptosis by caspase3 activity and TUNEL staining method. Endoplasmic reticulum stress markers were determined with quantitative RT-PCR, immunohistochemistry and immunoblot analysis. Results. After 6 weeks of treatment, vildagliptin treatment increased plasma active GLP-1 levels (22.63 +/- 1.19 vs. 11.69 +/- 0.44, P < 0.001), inhibited beta cell apoptosis as demonstrated by lower amounts of TUNEL staining nuclei (0.37 +/- 0.03 vs. 0.55 +/- 0.03, P < 0.01) as well as decreased caspase3 activity (1.48 +/- 0.11 vs. 2.67 +/- 0.13, P < 0.01) in islets of diabetic mice compared with untreated diabetic group. Further, vildagliptin treatment down-regulated several genes related to endoplasmic reticulum stress including TRIB3 (tribbles homolog 3) (15.9 +/- 0.4 vs. 33.3 +/- 1.7, x10(-3), P < 0.001), ATF-4(activating transcription factor 4) (0.83 +/- 0.06 vs. 1.42 +/- 0.02, P < 0.001) and CHOP(C/EBP homologous protein) (0.07 +/- 0.01 vs. 0.16 +/- 0.01, P < 0.001). Conclusions. Vildagliptin promoted beta cell survival in db/db mice in association with down-regulating markers of endoplasmic reticulum stress including TRIB3, ATF-4 as well as CHOP. (C) 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).