细胞膜 pH 值是连接环境线索与胰岛β细胞胰岛素加工和分泌的直接纽带。

Cell metabolism Pub Date : 2024-06-04 Epub Date: 2024-03-20 DOI:10.1016/j.cmet.2024.02.012
Yujiang Fang, Hexi Feng, Bowen Zhang, Shuwei Zhang, Yanjie Zhou, Pengcheng Hao, Zhongshu Zhou, Shanshan Zhou, Nan Li, Yi Hui, Lin Ma, Jie Xiong, Jinjin Wu, Ling Liu, Xiaoqing Zhang
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引用次数: 0

摘要

胰腺β细胞通过调节胰岛素的加工和分泌对葡萄糖波动做出积极反应。然而,这一过程是如何在多变的微环境和β细胞内在状态下进行精心调整的,以及其功能障碍是否与代谢性疾病有关,这些问题在很大程度上仍然令人难以捉摸。在这里,我们发现当葡萄糖挑战β细胞时,β细胞的细胞膜pH值(pHc)会升高,Smad5可通过其核胞质穿梭感应到这一点。如果β细胞中的Smad5发生病变,就会因胰岛素加工和分泌不足而导致高血糖和葡萄糖不耐受。Smad5 在调节胰岛素加工和分泌中的作用归因于其通过调节 V-ATP 酶活性实现颗粒酸化的非典型功能。对 Smad5 进行基因突变或给予碱性水以反映细胞膜碱化,可改善高脂饮食(HFD)处理小鼠的葡萄糖不耐受症。总之,我们的研究结果表明,pHc 是连接环境线索与 β 细胞中胰岛素加工和分泌的直接纽带。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Cytosolic pH is a direct nexus in linking environmental cues with insulin processing and secretion in pancreatic β cells.

Cytosolic pH is a direct nexus in linking environmental cues with insulin processing and secretion in pancreatic β cells.

Pancreatic β cells actively respond to glucose fluctuations through regulating insulin processing and secretion. However, how this process is elaborately tuned in circumstance of variable microenvironments as well as β cell-intrinsic states and whether its dysfunction links to metabolic diseases remain largely elusive. Here, we show that the cytosolic pH (pHc) in β cells is increased upon glucose challenge, which can be sensed by Smad5 via its nucleocytoplasmic shuttling. Lesion of Smad5 in β cells results in hyperglycemia and glucose intolerance due to insulin processing and secretion deficiency. The role of Smad5 in regulating insulin processing and secretion attributes to its non-canonical function by regulating V-ATPase activity for granule acidification. Genetic mutation of Smad5 or administration of alkaline water to mirror cytosolic alkalization ameliorated glucose intolerance in high-fat diet (HFD)-treated mice. Collectively, our findings suggest that pHc is a direct nexus in linking environmental cues with insulin processing and secretion in β cells.

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