Suppression of ROS Production by Exendin-4 in PSC Attenuates the High Glucose-Induced Islet Fibrosis

• Published in: PloS one Vol. 11; no. 12; p. e0163187
• Main Authors: Kim, Ji-Won, Park, Shin-Young, You, Young-Hye, Ham, Dong-Sik, Lee, Seung-Hwan, Yang, Hae Kyung, Jeong, In-Kyung, Ko, Seung-Hyun, Yoon, Kun-Ho
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.12.2016; Public Library of Science (PLoS)
• Subjects: Activation; Angiotensin; Angiotensin II; Angiotensin II - metabolism; Animals; Biology and Life Sciences; Cell growth; Cell Survival - drug effects; Complications and side effects; Consortia; Cyclic AMP-Dependent Protein Kinases - metabolism; Cytokines; Destruction; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Dosage and administration; Drug therapy; Endocrinology; Extracellular matrix; Fibrosis; Fibrosis - chemically induced; Fibrosis - metabolism; Fibrosis - pathology; Genetic aspects; Glucose; Glucose - pharmacology; Glucose Intolerance - metabolism; Glucose Intolerance - pathology; Glucose tolerance; Growth factors; Hyperglycemia; Hypoglycemic agents; Insulin; Internal medicine; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Kinases; Medicine; Medicine and Health Sciences; Metabolism; Pancreas; Pancreatic Stellate Cells - drug effects; Pancreatic Stellate Cells - metabolism; Pancreatic Stellate Cells - pathology; Pancreatitis; Peptides; Peptides - pharmacology; Phosphorylation; Physical Sciences; Physiological aspects; Protein kinase A; Proteins; Rats; Rats, Inbred OLETF; Reactive oxygen species; Reactive Oxygen Species - metabolism; Rodents; Science; Signal Transduction - drug effects; Stellate cells; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Type 2 diabetes; Venoms - pharmacology; South Korea
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0163187

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.