title: Suppression of ROS Production by Exendin-4 in PSC Attenuates the High Glucose-Induced Islet Fibrosis.
abstract: 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.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
authors.forename: Young-Hye
authors.initials: YH
authors.lastname: You
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
authors.forename: Dong-Sik
authors.initials: DS
authors.lastname: Ham
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hae Kyung
authors.initials: HK
authors.lastname: Yang
authors.affiliation: Division of Endocrinology & Metabolism, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.
authors.forename: In-Kyung
authors.initials: IK
authors.lastname: Jeong
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Ko
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Convergent Research Consortium for Immunologic Disease, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Korea.
authors.forename: Kun-Ho
authors.identifier: http://orcid.org/0000-0002-3806-4873
authors.initials: KH
authors.lastname: Yoon
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D000077270:Exenatide; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D020334:Rats, Inbred OLETF; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
chemical_list: D010455:Peptides; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D014688:Venoms; D000804:Angiotensin II; D000077270:Exenatide; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose