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

Cell Metab. 2024 Mar 15:S1550-4131(24)00059-7. doi: 10.1016/j.cmet.2024.02.012. Online ahead of print.ABSTRACTPancreatic 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.PMID:38513648 | DOI:10.1016/j.cmet.2024.02.012

Source: Cell Metabolism - March 21, 2024 Category: Cytology Authors: 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 Source Type: research