内质网应激信号分子IRE1α在胰岛β细胞中的功能及其作用机制

Pancreatic β-cells play a central role in glucose metabolism, and β-cell malfunction is a critical component underlying the pathogenesis of type 2 diabetes. The key function of β-cells is the regulated biosynthesis and adequate secretion of insulin in response to glucose levels. This is controlled by hormonal modulators such as glucagon-like peptide 1 (GLP1), which can potently stimulate glucose-dependent insulin production and secretion, and enhance β-cell proliferation while suppressing its apoptosis. Homeostasis in the endoplasmic reticulum (ER) is essential for the proper function and survival of β-cells. Accumulation of unfolded/misfolded proteins in the ER triggers the unfolded protein response (UPR), which reduces ER stress caused by the overload of protein folding. The ER-resident protein kinase IRE1α is a key sensor of ER stress. We previously found that GLP-1 could stimulate the phosphorylation of IRE1α in pancreatic β cells. To investigate the role of IRE1α in GLP1-dependent regulation of β-cell functions, we aim to generate β-cell-specific Ire1α knockout mice and examine the metabolic importance of IRE1α signaling in glucose homeostasis. Using the INS-1 β-cell line, we also attempt to explore the XBP1-dependent and -independent mechainism of IRE1α action in GLP1-mediated regulation of β-cell functions. This study will provide new insight into the link of ER stress to β-cell dysfunction and type 2 diabetes.

胰岛β细胞的功能调节及其衰损在2型糖尿病的发生发展中具有举足轻重的作用。大量研究表明，细胞内质网应激与β细胞的功能紊乱及其凋亡密切相关。内质网蛋白激酶IRE1α是内质网应激的关键感受器和效应分子，在胰岛β细胞中能应答于葡萄糖的刺激，并参与调控胰岛素的生物合成。我们前期的研究发现，胰高血糖素样肽1（GLP1）可以刺激胰岛β细胞中的IRE1α发生磷酸化，提示IRE1α信号通路在GLP1调节β细胞内分泌功能方面可能发挥重要的生理学功能。本项目拟利用胰岛β细胞系和β细胞特异性敲除IRE1α的小鼠模型，探索IRE1α在GLP-1促进胰岛β细胞的功能特性上所行使的调节作用，并解析IRE1α依赖于或不依赖于XBP1的下游信号机制。此项研究旨在深入了解内质网应激信号通路如何影响胰岛β细胞的功能，进而为阐明糖代谢平衡紊乱的病理学基础提供新的视角。