Deletion of the von Hippel-Lindau gene in pancreatic β cells impairs glucose homeostasis in mice
Deletion of the von Hippel-Lindau gene in pancreatic β cells impairs glucose homeostasis in mice
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DOI：
10.1172/jci26934
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发表时间：
2009-01-01
影响因子：
15.9
通讯作者：
Withers, Dominic J.
中科院分区：
文献类型：
--
作者：
Cantley, James;Selman, Colin;Withers, Dominic J.
葡萄糖引起的胰岛素分泌缺陷是2型糖尿病患者胰岛β细胞功能障碍的重要组成部分。由于线粒体氧化磷酸化在葡萄糖刺激的胰岛素分泌(GSIS)中起关键作用，氧敏感通路可能调节胰岛素的释放。Von Hippel-Lindau(VHL)蛋白控制低氧诱导因子(HIF)的降解，以协调细胞和组织对氧合变化的反应。为了确定这一途径在控制葡萄糖刺激的胰岛β细胞胰岛素释放中的作用，我们产生了在胰岛β细胞中缺乏VHL的小鼠(BETA VhlKO小鼠)和在胰腺中缺乏VHL的小鼠(PVhlKO小鼠)。两个品系的小鼠都出现了葡萄糖不耐受，并伴有胰岛素分泌受损。此外，β细胞或胰腺中VHL的缺失改变了与β细胞功能有关的基因的表达，包括那些涉及葡萄糖运输和糖酵解的基因，分离的βVhlKO和PVhlKO胰岛表现出葡萄糖摄取受损和葡萄糖代谢缺陷。糖稳态的异常依赖于Hif-1α表达的上调，而VHL缺陷的β细胞中HIF1a的缺失可恢复GSIS。与此一致的是，在小鼠β细胞系中表达激活的Hif-1α会损害GSIS。这些数据表明，VHL/HIF氧敏机制在葡萄糖稳态中起着关键作用，并且在胰岛氧合减少时激活这一途径可能有助于β细胞功能障碍。
Defective insulin secretion in response to glucose is an important component of the beta cell dysfunction seen in type 2 diabetes. As mitochondrial oxidative phosphorylation plays a key role in glucose-stimulated insulin secretion (GSIS), oxygen-sensing pathways may modulate insulin release. The von Hippel-Lindau (VHL) protein controls the degradation of hypoxia-inducible factor (HIF) to coordinate cellular and organismal responses to altered oxygenation. To determine the role of this pathway in controlling glucose-stimulated insulin release from pancreatic beta cells, we generated mice lacking Vhl in pancreatic beta cells (beta VhlKO mice) and mice lacking Vhl in the pancreas (PVhlKO mice). Both mouse strains developed glucose intolerance with impaired insulin secretion. Furthermore, deletion of Vhl in beta cells or the pancreas altered expression of genes involved in beta cell function, including those involved in glucose transport and glycolysis, and isolated beta VhlKO and PVhlKO islets displayed impaired glucose uptake and defective glucose metabolism. The abnormal glucose homeostasis was dependent on upregulation of Hif-1 alpha expression, and deletion of Hif1a in Vhl-deficient beta cells restored GSIS. Consistent with this, expression of activated Hif-1 alpha in a mouse beta cell line impaired GSIS. These data suggest that VHL/HIF oxygen-sensing mechanisms play a critical role in glucose homeostasis and that activation of this pathway in response to decreased islet oxygenation may contribute to beta cell dysfunction.