title: Vascular endothelial growth factor-mediated islet hypervascularization and inflammation contribute to progressive reduction of β-cell mass.
abstract: Type 2 diabetes (T2D) results from insulin resistance and inadequate insulin secretion. Insulin resistance initially causes compensatory islet hyperplasia that progresses to islet disorganization and altered vascularization, inflammation, and, finally, decreased functional β-cell mass and hyperglycemia. The precise mechanism(s) underlying β-cell failure remain to be elucidated. In this study, we show that in insulin-resistant high-fat diet-fed mice, the enhanced islet vascularization and inflammation was parallel to an increased expression of vascular endothelial growth factor A (VEGF). To elucidate the role of VEGF in these processes, we have genetically engineered β-cells to overexpress VEGF (in transgenic mice or after adeno-associated viral vector-mediated gene transfer). We found that sustained increases in β-cell VEGF levels led to disorganized, hypervascularized, and fibrotic islets, progressive macrophage infiltration, and proinflammatory cytokine production, including tumor necrosis factor-α and interleukin-1β. This resulted in impaired insulin secretion, decreased β-cell mass, and hyperglycemia with age. These results indicate that sustained VEGF upregulation may participate in the initiation of a process leading to β-cell failure and further suggest that compensatory islet hyperplasia and hypervascularization may contribute to progressive inflammation and β-cell mass loss during T2D.
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Agudo
authors.forename: Eduard
authors.initials: E
authors.lastname: Ayuso
authors.forename: Veronica
authors.initials: V
authors.lastname: Jimenez
authors.forename: Alba
authors.initials: A
authors.lastname: Casellas
authors.forename: Cristina
authors.initials: C
authors.lastname: Mallol
authors.forename: Ariana
authors.initials: A
authors.lastname: Salavert
authors.forename: Sabrina
authors.initials: S
authors.lastname: Tafuro
authors.forename: Mercè
authors.initials: M
authors.lastname: Obach
authors.forename: Albert
authors.initials: A
authors.lastname: Ruzo
authors.forename: Marta
authors.initials: M
authors.lastname: Moya
authors.forename: Anna
authors.initials: A
authors.lastname: Pujol
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D018450:Disease Progression; D005355:Fibrosis; D018014:Gene Transfer Techniques; D006965:Hyperplasia; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000098:blood supply* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011236:Prediabetic State / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D020033:Protein Isoforms; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse