GRP94 is an IGF-1R chaperone and regulates beta cell death in diabetes.
Do-Sung KimLili SongWenyu GouJisun KimBei LiuHua WeiRobin C Muise-HelmericksZihai LiHongjun WangPublished in: Cell death & disease (2024)
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.
Keyphrases
- cell death
- single cell
- endoplasmic reticulum stress
- type diabetes
- cell therapy
- cardiovascular disease
- cell cycle arrest
- cell surface
- glycemic control
- stem cells
- binding protein
- transcription factor
- cell proliferation
- metabolic syndrome
- mouse model
- gene expression
- signaling pathway
- amino acid
- oxidative stress
- heat shock protein
- heat shock
- weight loss
- single molecule