血管紧张素（1-7）激活MAS-1并上调囊性纤维化跨膜传导调节因子以促进胰腺β细胞分泌胰岛素：与2型糖尿病的关联
Angiotensin(1-7) activates MAS-1 and upregulates CFTR to promote insulin secretion in pancreatic β-cells: the association with type 2 diabetes.
作者信息
Zhang Xue-Lian, Zhao Xinyi, Wu Yong, Huang Wen-Qing, Chen Jun-Jiang, Hu Peijie, Liu Wei, Chen Yi-Wen, Hao Jin, Xie Rong-Rong, Chan Hsiao Chang, Ruan Ye Chun, Chen Hui, Guo Jinghui
机构信息
Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Department of Physiology, School of Medicine, Jinan University, Guangzhou, China.
出版信息
Endocr Connect. 2022 Jan 11;11(1):e210357. doi: 10.1530/EC-21-0357.
OBJECTIVE
The beneficial effect of angiotensin(1-7) (Ang(1-7)), via the activation of its receptor, MAS-1, has been noted in diabetes treatment; however, how Ang(1-7) or MAS-1 affects insulin secretion remains elusive and whether the endogenous level of Ang(1-7) or MAS-1 is altered in diabetic individuals remains unexplored. We recently identified an important role of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl- channel, in the regulation of insulin secretion. Here, we tested the possible involvement of CFTR in mediating Ang(1-7)'s effect on insulin secretion and measured the level of Ang(1-7), MAS-1 as well as CFTR in the blood of individuals with or without type 2 diabetes.
METHODS
Ang(1-7)/MAS-1/CFTR pathway was determined by specific inhibitors, gene manipulation, Western blotting as well as insulin ELISA in a pancreatic β-cell line, RINm5F. Human blood samples were collected from 333 individuals with (n = 197) and without (n = 136) type 2 diabetes. Ang(1-7), MAS-1 and CFTR levels in the human blood were determined by ELISA.
RESULTS
In RINm5F cells, Ang(1-7) induced intracellular cAMP increase, cAMP-response element binding protein (CREB) activation, enhanced CFTR expression and potentiated glucose-stimulated insulin secretion, which were abolished by a selective CFTR inhibitor, RNAi-knockdown of CFTR, or inhibition of MAS-1. In human subjects, the blood levels of MAS-1 and CFTR, but not Ang(1-7), were significantly higher in individuals with type 2 diabetes as compared to those in non-diabetic healthy subjects. In addition, blood levels of MAS-1 and CFTR were in significant positive correlation in type-2 diabetic but not non-diabetic subjects.
CONCLUSION
These results suggested that MAS-1 and CFTR as key players in mediating Ang(1-7)-promoted insulin secretion in pancreatic β-cells; MAS-1 and CFTR are positively correlated and both upregulated in type 2 diabetes.
目的
血管紧张素（1 - 7）（Ang(1 - 7)）通过激活其受体MAS - 1在糖尿病治疗中具有有益作用；然而，Ang(1 - 7)或MAS - 1如何影响胰岛素分泌仍不清楚，糖尿病个体中Ang(1 - 7)或MAS - 1的内源性水平是否改变也尚未得到探索。我们最近发现囊性纤维化跨膜电导调节因子（CFTR），一种cAMP激活的氯离子通道，在胰岛素分泌调节中起重要作用。在此，我们测试了CFTR是否可能参与介导Ang(1 - 7)对胰岛素分泌的影响，并测量了2型糖尿病患者和非糖尿病患者血液中Ang(1 - 7)、MAS - 1以及CFTR的水平。
方法
在胰腺β细胞系RINm5F中，通过特异性抑制剂、基因操作、蛋白质免疫印迹以及胰岛素酶联免疫吸附测定（ELISA）来确定Ang(1 - 7)/MAS - 1/CFTR通路。从333名个体（197名2型糖尿病患者和136名非糖尿病健康个体）采集人血样本。通过ELISA测定人血中Ang(1 - 7)、MAS - 1和CFTR水平。
结果
在RINm5F细胞中，Ang(1 - 7)诱导细胞内cAMP增加、cAMP反应元件结合蛋白（CREB）激活、增强CFTR表达并增强葡萄糖刺激的胰岛素分泌，这些作用被选择性CFTR抑制剂、CFTR的RNA干扰敲低或MAS - 1抑制所消除。在人类受试者中，与非糖尿病健康受试者相比，2型糖尿病患者血液中MAS - 1和CFTR水平显著升高，但Ang(1 - 7)水平未升高。此外，在2型糖尿病患者而非非糖尿病患者中，MAS - 1和CFTR的血液水平呈显著正相关。
结论
这些结果表明，MAS - 1和CFTR是介导Ang(1 - 7)促进胰腺β细胞胰岛素分泌的关键因素；MAS - 1和CFTR呈正相关，且在2型糖尿病中均上调。
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