葡萄糖代谢相关蛋白 1（GMRP1）通过激活 Akt 信号通路调节大鼠和小鼠胰岛β细胞的增殖和凋亡。
Glucose metabolism-related protein 1 (GMRP1) regulates pancreatic beta cell proliferation and apoptosis via activation of Akt signalling pathway in rats and mice.
机构信息
Department of Endocrinology, Huashan Hospital, Shanghai Medical College, Fudan University, 12 Wulumuqi Road Middle, Shanghai 200040, People's Republic of China.
出版信息
Diabetologia. 2011 Apr;54(4):852-63. doi: 10.1007/s00125-011-2048-1. Epub 2011 Jan 26.
AIMS/HYPOTHESIS: We attempted to elucidate the impacts on and possible mechanisms by which glucose metabolism-related protein 1 (GMRP1) affects beta cell survival.
METHODS
Adenovirus-mediated GMRP1 overproduction and siRNA-mediated knockdown were performed in INS-1E cells and rat islets, after which cell proliferation or apoptosis were determined, and phosphorylation of Akt and BCL2-associated agonist of cell death (BAD) investigated. INS-1E cells and rat islets were cultured at 5.6 (low) or 25 mmol/l (high) glucose for 24 or 48 h, and cell proliferation or apoptosis and GMRP1 levels were investigated. INS-1E cells were treated for 24 h with 0, 10, 50 and 100 nmol/l insulin, and GMRP1 levels were determined. After INS-1E cells were transfected with siRNA for 72 h, high glucose-induced cell proliferation and insulin-stimulated Akt phosphorylation were investigated. Glucose-infused rat models were established and beta cell proliferation and mass were evaluated. Levels of GMRP1, and phosphorylation of Akt and BAD were determined in glucose-infused islets. The GMRP1-mediated Akt pathway was also investigated in db/db mice.
RESULTS
Overproduction of GMRP1 promoted beta cell proliferation via increased phosphorylation of Akt. Knockdown of Gmrp1 (also known as Btbd10) reduced phosphorylation of Akt with enhanced beta cell apoptosis. High glucose increased GMRP1 levels and cell proliferation in INS-1E cells and islet cells. Knockdown of Gmrp1 decreased high glucose-induced cell proliferation and insulin-stimulated Akt phosphorylation. Increased GMRP1 levels were involved in the enhancement of beta cell proliferation and mass in glucose-infused islets. Decreased GMRP1 levels may participate in beta cell apoptosis of db/db mice.
CONCLUSIONS/INTERPRETATION: GMRP1 regulates pancreatic beta cell proliferation and apoptosis via activation of Akt signalling pathway.
目的/假设：我们试图阐明葡萄糖代谢相关蛋白 1（GMRP1）影响β细胞存活的作用及其可能机制。
方法
通过腺病毒介导的 GMRP1 过表达和 siRNA 介导的敲低，在 INS-1E 细胞和大鼠胰岛中进行实验，然后测定细胞增殖或凋亡，并研究 Akt 和 BCL2 相关细胞死亡激动剂（BAD）的磷酸化。将 INS-1E 细胞和大鼠胰岛分别在 5.6mmol/L（低）或 25mmol/L（高）葡萄糖中培养 24 或 48 小时，然后研究细胞增殖或凋亡和 GMRP1 水平。用 0、10、50 和 100nmol/L 胰岛素处理 INS-1E 细胞 24 小时，测定 GMRP1 水平。在 INS-1E 细胞转染 siRNA 72 小时后，研究高葡萄糖诱导的细胞增殖和胰岛素刺激的 Akt 磷酸化。建立 INS-1E 细胞过表达 GMRP1 的转基因小鼠模型，观察高糖诱导的细胞增殖和胰岛素刺激的 Akt 磷酸化变化。用葡萄糖输注建立大鼠胰岛模型，评估胰岛β细胞增殖和质量，测定葡萄糖输注胰岛中 GMRP1、Akt 和 BAD 的磷酸化水平。还研究了 db/db 小鼠中 GMRP1 介导的 Akt 通路。
结果
过表达 GMRP1 通过增加 Akt 的磷酸化促进β细胞增殖。敲低 Gmrp1（也称为 Btbd10）降低 Akt 的磷酸化，增加β细胞凋亡。高葡萄糖增加 INS-1E 细胞和胰岛细胞中的 GMRP1 水平和细胞增殖。敲低 Gmrp1 降低高葡萄糖诱导的细胞增殖和胰岛素刺激的 Akt 磷酸化。升高的 GMRP1 水平参与了葡萄糖输注胰岛中β细胞增殖和质量的增强。降低的 GMRP1 水平可能参与了 db/db 小鼠中β细胞的凋亡。
结论/解释：GMRP1 通过激活 Akt 信号通路调节胰腺β细胞的增殖和凋亡。
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