Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size.
Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size.
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DOI：
10.2337/db10-1194
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发表时间：
2011-03
期刊：
影响因子：
7.7
通讯作者：
Magnuson MA
中科院分区：
文献类型：
--
作者：
Gu Y;Lindner J;Kumar A;Yuan W;Magnuson MA
我们研究了Rictor/哺乳动物雷帕霉素靶蛋白复合物2（mTORC 2）在调节β细胞质量和功能中的作用，mTORC 2是磷脂酰肌醇-3-激酶（PI 3 K）/mTORC 2/AKT信号通路的关键组分。研究了具有Rictor或Pten的β细胞特异性缺失的小鼠，以确定缺失任一种或两种基因对β细胞质量和葡萄糖稳态的影响。Rictor敲除小鼠表现出轻度高血糖症和葡萄糖耐受不良，这是由β细胞质量、β细胞增殖、胰腺胰岛素含量和葡萄糖刺激的胰岛素分泌减少引起的。来自这些小鼠的胰岛表现出AKT-S473磷酸化降低和FoxO 1和p27蛋白丰度增加。相反，Pten null（βPtenKO）小鼠表现出由细胞增殖和大小增加引起的β细胞质量增加。虽然在缺乏Rictor和Pten的小鼠（βDKO）中β细胞质量正常，但其β细胞大于βPtenKO小鼠中的β细胞。尽管βDKO小鼠中的β细胞增殖率低于βPtenKO小鼠，但AKT-T308的磷酸化增加了12倍。通过mTORC 2/pAKT-S473的PI 3 K/AKT信号传导在维持正常β细胞群中起关键作用。AKT-S473的磷酸化，通过负调节AKT-T308的磷酸化，对于维持响应于增殖刺激的β细胞增殖和细胞大小之间的平衡至关重要。
We examined the role of Rictor/mammalian target of rapamycin complex 2 (mTORC2), a key component of the phosphotidylinositol-3-kinase (PI3K)/mTORC2/AKT signaling pathway, in regulating both β-cell mass and function. Mice with β-cell–specific deletions of Rictor or Pten were studied to determine the effects of deleting either or both genes on β-cell mass and glucose homeostasis. Rictor null mice exhibited mild hyperglycemia and glucose intolerance caused by a reduction in β-cell mass, β-cell proliferation, pancreatic insulin content, and glucose-stimulated insulin secretion. Islets from these mice exhibited decreased AKT-S473 phosphorylation and increased abundance of FoxO1 and p27 proteins. Conversely, Pten null (βPtenKO) mice exhibited an increase in β-cell mass caused by increased cellular proliferation and size. Although β-cell mass was normal in mice lacking both Rictor and Pten (βDKO), their β-cells were larger than those in the βPtenKO mice. Even though the β-cell proliferation rate in the βDKO mice was lower than in the βPtenKO mice, there was a 12-fold increase the phosphorylation of AKT-T308. PI3K/AKT signaling through mTORC2/pAKT-S473 plays a key role in maintaining normal β-cell mass. The phosphorylation of AKT-S473, by negatively regulating that of AKT-T308, is essential for maintaining a balance between β-cell proliferation and cell size in response to proliferative stimuli.