摘要
PTEN， phosphatidylinositol-3-kinase/AKT 小径的一个否定管理者，是胰岛素发信号的一个重要调节的人。决定胰腺的 Pten 的新陈代谢的函数，我们产生了胰特定的 Pten 大美人(PPKO ) 鼠标。PPKO 老鼠扩大了胰并且提高了 acinar 房间的增长。他们也展出了低血糖症， hypoinsulinemia，和改变的氨基的新陈代谢。尤其是， PPKO 老鼠证明 streptozotocin (STZ ) 的推迟的发作导致了糖尿病，到 high-fat-diet (HFD ) 的偏导性的抵抗导致了糖尿病。在 PPKO 老鼠为抵抗调查机制到导致 HFD 的多糖症，我们在主要胰岛素应答的纸巾评估了 AKT phosphorylation：肝，肌肉，和脂肪。我们发现在胰的 Pten 损失引起在肝发信号的 AKT 的举起。AKT 和它的下游的底层 GSK3 尾的 phosphorylation 在 PPKO 老鼠的肝被增加，当没有 Pten 等位基因的可检测的切除， PTEN 水平在 PPKO 老鼠的肝被减少时。戏剧性地揭示的 Proteomics 分析减少了在 PPKO 老鼠的肝 78-kDa 铺平调整葡萄糖的蛋白质(GRP78 ) ，它可以也贡献用 HFD 喂的 PPKO 老鼠的更低的血葡萄糖水平。一起，我们的调查结果在新陈代谢的规定在肝揭示新奇回答到胰腺的缺点，把一种新尺寸加到理解糖尿病抵抗。
PTEN, a negative regulator of the phosphatidylinositol-3-kinase/AKT pathway, is an important modulator of insulin signaling. To determine the metabolic function of pancreatic Pten, we generated pancreas-specific Pten knockout （PPKO） mice. PPKO mice had enlarged pancreas and elevated proliferation of acinar cells. They also exhibited hypoglycemia, hypoinsulinemia, and altered amino metabolism. Notably, PPKO mice showed delayed onset of streptozotocin （STZ）-induced diabetes and sex-biased resistance to high-fat-diet （HFD）-induced diabetes. To investigate the mechanism for the resistance to HFD-induced hyperglycemia in PPKO mice, we evaluated AKT phosphorylation in major insulin-responsive tissues： the liver, muscle, and fat. We found that Pten loss in the pancreas causes the elevation of AKT signaling in the liver. The phosphorylation of AKT and its downstream substrate GSK3β was increased in the liver of PPKO mice, while PTEN level was decreased without detectable excision of Pten allele in the liver of PPKO mice. Proteomics analysis revealed dramatically decreased level of 78-kDa glucose-regulated protein （GRP78） in the liver of PPKO mice, which may also contribute to the lower blood glucose level of PPKO mice fed with HFD. Together, our findings reveal a novel response in the liver to pancreatic defect in metabolic regulation, adding a new dimension to understanding diabetes resistance.
基金
This research was supported by grants from the Ministry of Ed- ucation （705001）, National Basic Research Program of China （973 Program 2009CB941200）, National Natural Science Foundation of China （30830061 and 30421004）, and a 111 project to H Deng. We thank Dr Tak Wah Mak （University of Alberta, Canada） for kindly providing the Ptern mice, Dr Guoqiang Gu （Vanderbilt University, USA） for kindly providing the plasmid of Pdxl-Cre, and Dr C Wright （Vanderbilt University, USA） for the PDX1 antibody. We thank the Model Animal Research Center of Nanjing University for B6
129-Gt（ROSA）26Sor tm/Sho/J mice and the Research Center for Proteome Analysis for proteomics analysis. We thank Dr Matt Stremlau, Dr Hui Zhang, Jun Cai, Han Qin, Jian Li, Yan Shi, Haisheng Zhou, and Fei Ye for their critical reading of the manu- script. We also thank Wei Jiang, Yushan Guo, Jie Yang, Chengyan Wang, Hui Zhang, and other colleagues in our laboratory for providing technical assistance and advice during the experiments.
