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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cytokines / metabolism
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Diabetes Mellitus, Type 2 / etiology
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Diabetes Mellitus, Type 2 / immunology
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Diabetes Mellitus, Type 2 / metabolism
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Diabetes Mellitus, Type 2 / pathology
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Diet, High-Fat / adverse effects
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Disease Progression
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Fibrosis
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Gene Transfer Techniques
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Hyperplasia
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Insulin Resistance
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Insulin-Secreting Cells / metabolism
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Insulin-Secreting Cells / pathology
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Islets of Langerhans / blood supply*
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Islets of Langerhans / immunology
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Islets of Langerhans / metabolism*
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Islets of Langerhans / pathology
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Macrophages / immunology
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Macrophages / metabolism
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Macrophages / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Neovascularization, Pathologic / immunology
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Neovascularization, Pathologic / metabolism*
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Neovascularization, Pathologic / pathology
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Prediabetic State / etiology
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Prediabetic State / immunology
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Prediabetic State / metabolism*
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Prediabetic State / pathology
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Protein Isoforms / biosynthesis
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / metabolism
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Up-Regulation*
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Vascular Endothelial Growth Factor A / biosynthesis*
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Cytokines
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Protein Isoforms
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Recombinant Proteins
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse