title: Dipeptidyl peptidase IV inhibition activates CREB and improves islet vascularization through VEGF-A/VEGFR-2 signaling pathway.
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.
authors.affiliation: Third Medical Clinic and Policlinic, Justus-Liebig-University, Giessen, Germany.
authors.forename: Balaji
authors.initials: B
authors.lastname: Samikannu
authors.affiliation: CRTD / DFG- Center for Regenerative Therapies Dresden, Paul Langerhans Institut Dresden, Dresden, Germany.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Chen
authors.affiliation: Third Medical Clinic and Policlinic, Justus-Liebig-University, Giessen, Germany.
authors.forename: Neelam
authors.initials: N
authors.lastname: Lingwal
authors.affiliation: Third Medical Clinic and Policlinic, Justus-Liebig-University, Giessen, Germany.
authors.forename: Manju
authors.initials: M
authors.lastname: Padmasekar
authors.affiliation: University Hospital Erlangen, Experimental Renal and Cardiovascular Research, Nephropathology Division, Department of Pathology, Erlangen, Germany.
authors.forename: Felix B
authors.initials: FB
authors.lastname: Engel
authors.affiliation: Third Medical Clinic and Policlinic, Justus-Liebig-University, Giessen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Linn
mesh_terms: D000818:Animals; D001786:Blood Glucose; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D007328:Insulin / Q000096:biosynthesis; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000068900:Sitagliptin Phosphate; D013552:Swine; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D017362:Cyclic AMP Response Element-Binding Protein; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D011719:Pyrazines; D014230:Triazoles; D042461:Vascular Endothelial Growth Factor A; D052216:Glucagon-Like Peptide 1; D040301:Vascular Endothelial Growth Factor Receptor-2; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate