Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA.
Microbiology and Immunology, Medical University of South Carolina, Charleson, SC, 29425, USA.
Cell Death Dis. 2024 May 29;15(5):374. doi: 10.1038/s41419-024-06754-y.
High workload-induced cellular stress can cause pancreatic islet β cell death and dysfunction, or β cell failure, a hallmark of type 2 diabetes mellitus. Thus, activation of molecular chaperones and other stress-response genes prevents β cell failure. To this end, we have shown that deletion of the glucose-regulated protein 94 (GRP94) in Pdx1 pancreatic progenitor cells led to pancreas hypoplasia and reduced β cell mass during pancreas development in mice. Here, we show that GRP94 was involved in β cell adaption and compensation (or failure) in islets from leptin receptor-deficient (db/db) mice in an age-dependent manner. GRP94-deficient cells were more susceptible to cell death induced by various diabetogenic stress conditions. We also identified a new client of GRP94, insulin-like growth factor-1 receptor (IGF-1R), a critical factor for β cell survival and function that may mediate the effect of GRP94 in the pathogenesis of diabetes. This study has identified essential functions of GRP94 in β cell failure related to diabetes.
高工作量引起的细胞应激会导致胰岛β细胞死亡和功能障碍，或β细胞衰竭，这是 2 型糖尿病的标志。因此，激活分子伴侣和其他应激反应基因可以防止β细胞衰竭。为此，我们已经表明，在小鼠胰腺发育过程中，Pdx1 胰腺祖细胞中葡萄糖调节蛋白 94 (GRP94) 的缺失导致胰腺发育不良和β细胞数量减少。在这里，我们表明 GRP94 以年龄依赖的方式参与了瘦素受体缺陷 (db/db) 小鼠胰岛中的β细胞适应和代偿 (或衰竭)。GRP94 缺陷细胞对各种致糖尿病应激条件诱导的细胞死亡更为敏感。我们还鉴定了 GRP94 的一个新的客户，胰岛素样生长因子-1 受体 (IGF-1R)，它是β细胞存活和功能的关键因素，可能介导 GRP94 在糖尿病发病机制中的作用。这项研究确定了 GRP94 在与糖尿病相关的β细胞衰竭中的重要功能。
