Vascular Endothelial Growth Factor-Mediated Islet Hypervascularization and Inflammation Contribute to Progressive Reduction of β-Cell Mass

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 beta-cell mass and hyperglycemia. The precise mechanism(s) underlying beta-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 beta-cells to overexpress VEGF (in transgenic mice or after adeno-associated viral vector-mediated gene transfer). We found that sustained increases in beta-cell VEGF levels led to disorganized, hypervascularized, and fibrotic islets, progressive macrophage infiltration, and proinflammatory cytokine production, including tumor necrosis factor-alpha and interleukin-1 beta. This resulted in impaired insulin secretion, decreased beta-cell mass, and hyperglycemia with age. These results indicate that sustained VEGF upregulation may participate in the initiation of a process leading to beta-cell failure and further suggest that compensatory islet hyperplasia and hypervascularization may contribute to progressive inflammation and beta-cell mass loss during T2D. Diabetes 61:2851-2861, 2012