Proper mTORC1 Activity Is Required for Glucose Sensing and Early Adaptation in Human Pancreatic β Cells
Proper mTORC1 Activity Is Required for Glucose Sensing and Early Adaptation in Human Pancreatic β Cells
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人类胰腺 β 细胞的葡萄糖感应和早期适应需要适当的 mTORC1 活性
DOI：
10.1210/clinem/dgaa786
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发表时间：
2021-01-23
影响因子：
5.8
通讯作者：
Wang, Qidi
中科院分区：
文献类型：
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作者：
Ni, Qicheng;Song, Jiaxi;Wang, Qidi
雷帕霉素复合体I （mTORC1）的机制靶点对啮齿动物β细胞的身份和功能至关重要。然而，其与人类糖尿病生理病理的可能相关性尚不清楚。目的了解mTORC1参与人β细胞在糖尿病前期和糖尿病中的作用。我们评估了12例非糖尿病（ND）、11例空腹血糖受损（IFG）和11例血糖控制的2型糖尿病（T2D）患者胰腺切片胰岛的PS6免疫荧光强度。我们还评估了新发糖尿病db/db小鼠β细胞中mTORC1活性的动态变化。结果人胰岛细胞mTORC1活性存在细胞间异质性。胰岛mTORC1活性与ND中FBG独立且正相关，但与IFG和T2D无关。此外，我们没有发现T2D和ND之间mTORC1活性的显著变化。值得注意的是，胰岛mTORC1活性在IFG中明显高于ND。我们进一步根据他们的胰岛PS6水平对IFG个体进行分层，发现与IFG-PS6（低）相比，IFG-PS6（高）在β细胞中表现出显著更高的尿皮质蛋白3和葡萄糖转运蛋白2表达。与非糖尿病小鼠相比，我们还检测到糖尿病前期db/db小鼠的mTORC1活性显著增加。有趣的是，mTORC1活性决定了db/db小鼠的β细胞适应或失败：在db/db小鼠的糖尿病进展过程中，发现胰岛mTORC1活性与空腹血糖水平之间存在强烈的负相关。我们的发现强调了胰岛mTORC1在人类T2D中β细胞适应/失败的动态反应。
Context The mechanistic target of rapamycin complex I (mTORC1) is crucial for beta-cell identity and function in rodents. However, its possible relevance to the physiopathology of diabetes in humans remains unclear.Objective This work aimed to understand the participation of mTORC1 in human beta cells in prediabetes and diabetes.Design We evaluated the PS6 immunofluorescence intensity in islets of pancreatic sections from 12 nondiabetic (ND), 11 impaired fasting glucose (IFG), and 11 glycemic-controlled type 2 diabetic (T2D) individuals. We also assessed the dynamic change of mTORC1 activity in beta cells of db/db mice with new-onset diabetes.Results There exists intercellular heterogeneity of mTORC1 activities in human islets. Islet mTORC1 activity was independently and positively correlated with FBG in ND, but not in IFG and T2D. Moreover, we did not detect significant change in mTORC1 activities between T2D and ND. Of note, the islet mTORC1 activities were significantly higher in IFG than in ND. We further stratified IFG individuals according to their islet PS6 levels and found that IFG-PS6(high) exhibited remarkably higher urocortin3 and glucose transporter 2 expression in their beta cells compared to IFG-PS6(low). Consistently, we also detected a significant increase in mTORC1 activities in prediabetic db/db mice compared to nondiabetic littermates. Interestingly, mTORC1 activities determined beta-cell adaptation or failure in db/db mice: A strong negative correlation was found between islet mTORC1 activities and fasting glucose levels in db/db mice during their diabetes progression.Conclusions Our finding highlights a dynamic islet mTORC1 response in beta-cell adaption/failure in human T2D.