Open AccessSuppression of ROS Production by Exendin-4 in PSC Attenuates the High Glucose-Induced Islet Fibrosis
Author(s) -
Ji-Won Kim,
Shin-Young Park,
YoungHye You,
Dong-Sik Ham,
SeungHwan Lee,
Hae Kyung Yang,
InKyung Jeong,
SeungHyun Ko,
KunHo Yoon
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0163187
Subject(s) - islet , downregulation and upregulation , endocrinology , medicine , mapk/erk pathway , fibrosis , angiotensin ii , chemistry , diabetes mellitus , receptor , signal transduction , biochemistry , gene
Pancreatic stellate cells (PSCs) play a major role to fibrotic islet destruction observed in diabetic patients and animal model of diabetes. Exendin-4 (Ex-4) is a potent insulinotropic agent and has been approved for the treatment of type 2 diabetes. However, there have been no reports demonstrating the effects of Ex-4 on pancreatic islet fibrosis. In this study, Ex-4 treatment clearly attenuated fibrotic islet destruction and improved glucose tolerance and islet survival. GLP-1 receptor expression was upregulated during activation and proliferation of PSCs by hyperglycemia. The activation of PKA pathway by Ex-4 plays a role in ROS production and angiotensin II (Ang II) production. Exposure to high glucose stimulated ERK activation and Ang II-TGF- β1 production in PSCs. Interestingly, Ex-4 significantly reduced Ang II and TGF-β1 production by inhibition of ROS production but not ERK phosphorylation. Ex-4 may be useful not only as an anti-diabetic agent but also as an anti-fibrotic agent in type 2 diabetes due to its ability to inhibit PSC activation and proliferation and improve islet fibrosis in OLETF rats.