Impaired insulin secretion in vivo but enhanced insulin secretion from isolated islets in pancreatic beta cell-specific vascular endothelial growth factor-A knock-out mice
Impaired insulin secretion in vivo but enhanced insulin secretion from isolated islets in pancreatic beta cell-specific vascular endothelial growth factor-A knock-out mice
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DOI：
10.1007/s00125-006-0512-0
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发表时间：
2007-02-01
期刊：
影响因子：
8.2
通讯作者：
Watada, H.
中科院分区：
文献类型：
--
作者：
Iwashita, N.;Uchida, T.;Watada, H.
目的/假设内皮细胞被认为是正常胰腺β细胞功能所必需的。然而，目前还没有报道显示其对β细胞功能的重要性，我们使用β细胞特异性血管内皮生长因子-A基因被破坏的小鼠，研究胰岛血管结构和β细胞功能之间的关系，β细胞特异性血管内皮生长因子-A基因被破坏的小鼠胰岛血管密度降低，内皮开窗形成受损。虽然它们的空腹血糖和体重与对照小鼠相当，但它们的葡萄糖和甲苯磺丁脲诱导的快速胰岛素释放受损，从而导致葡萄糖耐受不良。另一方面，葡萄糖和KCl增强了从这些小鼠分离的胰岛分泌的胰岛素水平。此外，在胰岛中可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体的产生增加。胰岛中胰岛素含量和胰岛素I及胰腺十二指肠同源框1 mRNA的表达也增加。我们的研究结果表明，由于β细胞中血管内皮生长因子-A表达减少而导致的血管质量和数量异常可能是胰岛素分泌受损而不损害β细胞功能的原因。
Aims/hypothesis Endothelial cells are considered to be essential for normal pancreatic beta cell function. However, there have been no reports showing their importance for beta cell function.Using mice with disrupted vascular endothelial growth factor-A gene specifically in beta cells, we investigated the relation between islet vascular structure and beta cell function.Mice with disrupted vascular endothelial growth factor-A gene specifically in beta cells had reduced islet vascular density with impaired formation of endothelial fenestration. While their fasting glucose and body weight were comparable with control mice, their glucose- and tolbutamide-induced rapid insulin release were impaired, thus resulting in glucose intolerance. On the other hand, glucose and KCl enhanced the levels of insulin secreted from islets isolated from these mice. In addition, the production of soluble N-ethylmaleimide-sensitive factor attachment protein receptors in the islets was increased. Insulin content and expression of insulin I and pancreas duodenum homeobox 1 mRNA in the islets were also increased.Our results indicate that an abnormal quality and quantity of blood vessels due to reduced expression of vascular endothelial growth factor-A in beta cells could be a cause of impaired insulin secretion without impairment of beta cell function.