Distinct roles of systemic and local actions of insulin on pancreatic β-cells.
Distinct roles of systemic and local actions of insulin on pancreatic β-cells.
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DOI：
10.1016/j.metabol.2017.12.017
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Miki T
中科院分区：
文献类型：
--
作者：
Kitamoto T;Sakurai K;Lee EY;Yokote K;Accili D;Miki T
胰腺β细胞的质量和功能对葡萄糖稳态至关重要。它们的调节机制主要是在β细胞数量减少的实验条件下研究的，如β细胞消融和部分胰腺切除术。在本研究中，我们建立了过量异位β细胞的小鼠模型，并分析了其对β细胞质量和存活的影响。采用胰腺β细胞系MIN6生成的假胰岛进行亚肾移植（SRT）或胰腺内移植（IPT），观察小鼠内分泌胰腺的形态和功能变化。采用RipCre:Rosa26-tdTomato小鼠，追踪胰腺β细胞移植后的细胞命运。通过使用MIN6细胞，我们评估了细胞外葡萄糖、膜电位和胰岛素信号在β细胞存活中的作用。SRT小鼠出现严重的进行性低血糖，并伴有胰岛素阳性（Ins+）细胞数量的显著减少和Ins+细胞凋亡的明显增加。在MIN6细胞的体外实验中，胰岛素信号阻断可诱导细胞死亡，表明β细胞存活需要局部胰岛素作用。事实上，IPT(即。与SRT诱导的相比，靠近内源性β细胞的移植导致的凋亡细胞较少。另一方面，在SRT和IPT小鼠中，β细胞质量的减少与血糖水平的降低成正比，提示全身性高胰岛素血症诱导的低血糖有贡献。胰岛素分别通过对β细胞的局部作用和全身作用在β细胞存活和β细胞质量调节中发挥着不同的作用。
Pancreatic β-cell mass and function are critical in glucose homeostasis. Their regulatory mechanisms have been studied principally under experimental conditions of reduced β-cell numbers, such as β-cell ablation and partial pancreatectomy. In the present study, we generated an opposite mouse model with an excessive amount of ectopic β-cells, and analyzed its consequence on β-cell mass and survival. Mice underwent sub-renal transplantation (SRT) of pseudo-islets generated from a pancreatic β-cell line MIN6 or intra-pancreatic transplantation (IPT) of MIN6 cells, and morphological and functional changes of their endocrine pancreata were analyzed. Cellular fate of pancreatic β-cells after transplantation was traced using RipCre:Rosa26-tdTomato mice. By using MIN6 cells, we evaluated the roles of extracellular glucose, membrane potential, and insulin signaling on β-cell survival. SRT mice developed severe, progressive hypoglycemia associated with marked reduction in insulin-positive (Ins+) cell mass and apparent increase in apoptotic Ins+ cells. In in vitro experiments of MIN6 cells, insulin signaling blockade potently induced cell death, suggesting that local insulin action is required for β-cell survival.In fact, IPT(i.e. transplantation closeto endogenous β-cells)resulted in fewer apoptotic Ins+ cells compared with those induced by SRT. On the other hand, β-cell mass was decreased in proportion to the decrease in blood glucose levels in both SRT and IPT mice, suggesting a contribution of hypoglycemia induced by systemic hyperinsulinemia. Insulin plays distinct roles in β-cell survival and β-cell mass regulation through its local and systemic actions on β-cells, respectively.
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影响因子：
4.6
作者：
Lee EY;Sakurai K;Zhang X;Toda C;Tanaka T;Jiang M;Shirasawa T;Tachibana K;Yokote K;Vidal-Puig A;Minokoshi Y;Miki T
通讯作者：
Miki T
影响因子：
5.3
作者：
Assmann, Anke;Ueki, Kohjiro;Kulkarni, Rohit N.
通讯作者：
Kulkarni, Rohit N.
影响因子：
9.8
作者：
Chen, Liang;Pei, Jian-Hao;Yang, Hua-Zhang
通讯作者：
Yang, Hua-Zhang
影响因子：
15.9
作者：
Hoorens, A;VandeCasteele, M;Pipeleers, D
通讯作者：
Pipeleers, D
影响因子：
64.5
作者：
GLUZMAN, Y
通讯作者：
GLUZMAN, Y