Conditional hypovascularization and hypoxia in islets do not overtly influence adult β-cell mass or function.
Conditional hypovascularization and hypoxia in islets do not overtly influence adult β-cell mass or function.
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DOI：
10.2337/db12-1827
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发表时间：
2013-12
期刊：
影响因子：
7.7
通讯作者：
Heimberg H
中科院分区：
文献类型：
--
作者：
D'Hoker J;De Leu N;Heremans Y;Baeyens L;Minami K;Ying C;Lavens A;Chintinne M;Stangé G;Magenheim J;Swisa A;Martens G;Pipeleers D;van de Casteele M;Seino S;Keshet E;Dor Y;Heimberg H
通常认为，胰岛的血管化和氧合对于维持最佳β细胞质量和功能是必不可少的，并且血管内皮生长因子（VEGF）的信号传导对于胰腺发育、胰岛素基因表达/分泌和（代偿性）β细胞增殖是至关重要的。设计了一种新的小鼠模型，允许β细胞有条件地产生人sFlt 1，以捕获VEGF并研究VEGF信号传导的时间依赖性抑制对成年β细胞命运和代谢的影响。成体β细胞分泌sFlt 1导致胰岛内血管快速消退和缺氧。除了胰岛素释放减弱外，β细胞还显示出应对这些假定不利条件的显著能力：即使在长时间的血管消融后，基础和刺激血糖水平也仅略微升高，而β细胞增殖和质量仍不受影响。此外，血管消融并不能阻止部分胰管结扎或部分胰腺切除术造成的严重胰腺损伤后β细胞的生成。因此，我们的数据反对血管在维持成人β细胞生成和功能方面的主要作用，限制了它们在促进快速和充分的胰岛素输送方面的重要性。
It is generally accepted that vascularization and oxygenation of pancreatic islets are essential for the maintenance of an optimal β-cell mass and function and that signaling by vascular endothelial growth factor (VEGF) is crucial for pancreas development, insulin gene expression/secretion, and (compensatory) β-cell proliferation. A novel mouse model was designed to allow conditional production of human sFlt1 by β-cells in order to trap VEGF and study the effect of time-dependent inhibition of VEGF signaling on adult β-cell fate and metabolism. Secretion of sFlt1 by adult β-cells resulted in a rapid regression of blood vessels and hypoxia within the islets. Besides blunted insulin release, β-cells displayed a remarkable capacity for coping with these presumed unfavorable conditions: even after prolonged periods of blood vessel ablation, basal and stimulated blood glucose levels were only slightly increased, while β-cell proliferation and mass remained unaffected. Moreover, ablation of blood vessels did not prevent β-cell generation after severe pancreas injury by partial pancreatic duct ligation or partial pancreatectomy. Our data thus argue against a major role of blood vessels to preserve adult β-cell generation and function, restricting their importance to facilitating rapid and adequate insulin delivery.
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