Dipeptidyl Peptidase IV Inhibition Activates CREB and Improves Islet Vascularization through VEGF-A/VEGFR-2 Signaling Pathway
Open Access
- 11 December 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (12), e82639
- https://doi.org/10.1371/journal.pone.0082639
Abstract
Substitution of pancreatic islets is a potential therapy to treat diabetes and it depends on reconstitution of islet’s capillary network. In this study, we addressed the question whether stabilization of Glucagon-Like-Peptide-1 (GLP-1) by inhibiting Dipeptidyl Peptidase-IV (DPP-IV) increases β-cell mass by modulating vascularization. Mouse or porcine donor islets were implanted under kidney capsule of diabetic mice treated with DPP-IV inhibitor sitagliptin. Grafts were analyzed for insulin production, β-cell proliferation and vascularization. In addition, the effect of sitagliptin on sprouting and Vascular Endothelial Growth Factor (VEGF)-A expression was examined ex vivo. The cAMP response element-binding (CREB) and VEGF-A/ Vascular Endothelial Growth Factor Receptor (VEGFR)-2 signaling pathway leading to islet vascularization was explored. Sitagliptin increased mean insulin content of islet grafts and area of insulin-positive tissue as well as β-cell proliferation. Interestingly, sitagliptin treatment also markedly increased endothelial cell proliferation, microvessel density and blood flow. Finally, GLP-1 (7-36) stimulated sprouting and VEGF expression, which was significantly enhanced by sitagliptin- mediated inhibition of DPP-IV. Our in vivo data demonstrate that sitagliptin treatment phosphorylated CREB and induced islet vascularization through VEGF-A/VEGFR-2 signaling pathway. This study paves a new pathway for improvement of islet transplantation in treating diabetes mellitus.Keywords
This publication has 42 references indexed in Scilit:
- Improvement of Rat Islet Viability during Transplantation: Validation of Pharmacological Approach to Induce VEGF OverexpressionCell Transplantation, 2011
- mTOR links incretin signaling to HIF induction in pancreatic beta cellsProceedings of the National Academy of Sciences of the United States of America, 2011
- Improved Outcome of Islet Transplantation in Partially Pancreatectomized Diabetic Mice by Inhibition of Dipeptidyl Peptidase-4 With SitagliptinPancreas, 2011
- Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptorMolecular and Cellular Endocrinology, 2010
- Lesion-targeted thrombopoietin potentiates vasculogenesis by enhancing motility and enlivenment of transplanted endothelial progenitor cells via activation of Akt/mTOR/p70S6kinase signaling pathwayJournal of Molecular and Cellular Cardiology, 2008
- Revascularization of Transplanted IsletsDiabetes, 2008
- GLP-1 receptor signaling protects pancreatic beta cells in intraportal islet transplant by inhibiting apoptosisBiochemical and Biophysical Research Communications, 2008
- cAMP promotes pancreatic β-cell survival via CREB-mediated induction of IRS2Genes & Development, 2003
- VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodiaThe Journal of cell biology, 2003
- Angiogenic capacity of endothelial cells in islets of LangerhansThe FASEB Journal, 2003