| First Author | Darden CM | Year | 2022 |
| Journal | iScience | Volume | 25 |
| Issue | 4 | Pages | 104125 |
| PubMed ID | 35402865 | Mgi Jnum | J:323405 |
| Mgi Id | MGI:7262507 | Doi | 10.1016/j.isci.2022.104125 |
| Citation | Darden CM, et al. (2022) Calcineurin/NFATc2 and PI3K/AKT signaling maintains beta-cell identity and function during metabolic and inflammatory stress. iScience 25(4):104125 |
| abstractText | Pancreatic islets respond to metabolic and inflammatory stress by producing hormones and other factors that induce adaptive cellular and systemic responses. Here we show that intracellular Ca(2+) ([Ca(2+)]i) and ROS signals generated by high glucose and cytokine-induced ER stress activate calcineurin (CN)/NFATc2 and PI3K/AKT to maintain beta-cell identity and function. This was attributed in part by direct induction of the endocrine differentiation gene RFX6 and suppression of several beta-cell "disallowed" genes, including MCT1. CN/NFATc2 targeted p300 and HDAC1 to RFX6 and MCT1 promoters to induce and suppress gene transcription, respectively. In contrast, prolonged exposure to stress, hyperstimulated [Ca(2+)]i, or perturbation of CN/NFATc2 resulted in downregulation of RFX6 and induction of MCT1. These findings reveal that CN/NFATc2 and PI3K/AKT maintain beta-cell function during acute stress, but beta-cells dedifferentiate to a dysfunctional state upon loss or exhaustion of Ca(2+)/CN/NFATc2 signaling. They further demonstrate the utility of targeting CN/NFATc2 to restore beta-cell function. |
