Vascular Endothelial Growth Factor–Mediated Islet Hypervascularization and Inflammation Contribute to Progressive Reduction of β-Cell Mass
- Judith Agudo1,2,3,
- Eduard Ayuso1,2,3,
- Veronica Jimenez1,2,3,
- Alba Casellas1,2,3,
- Cristina Mallol1,2,3,
- Ariana Salavert1,2,
- Sabrina Tafuro1,2,3,†,
- Mercè Obach1,2,3,
- Albert Ruzo1,2,3,
- Marta Moya1,2,3,
- Anna Pujol1,3 and
- Fatima Bosch1,2,3⇓
- 1Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Barcelona, Spain
- 2Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Barcelona, Spain
- 3Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain
- Corresponding author: Fatima Bosch, .
E.A. and V.J. contributed equally to this work.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0134/-/DC1.
- Received February 8, 2012.
- Accepted May 29, 2012.
- © 2012 by the American Diabetes Association.
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