Metabolic Insufficiency Caused By Cellular Stresses Is Implicated in Beta-Cell Dedifferentiation in the Mouse Model of Wolfram Syndrome

Pancreatic beta cell loss is associated with augmented ER and oxidative stresses in Wolfram syndrome caused by mutations in the WFS1. In the Wfs1 -/- mice, beta cells become dedifferentiated and revert to endocrine progenitor-like cells, and a subset of them takes alpha cell fate. Such beta cell plasticity appears after nursing, independently of hyperglycemia, and becomes more apparent along with diabetes progression accompanied with no significant increase in apoptosis. We have found that genetic inhibition of Txnip, which is a stress response molecule involving in various cellular processes, preserved beta cell mass and maintained glucose homeostasis in the Wfs1 -/- mice. This suggests its roles in the regulation of beta cell plasticity in the setting of Wfs1 deficiency. One clue to the mechanisms underlying beta cell dedifferentiation was the paradoxical reduction of acetyl-CoA, citrate and ATP content in the Wfs1 -/- islets in spite of the enhanced glycolysis with an increase in pyruvate. This metabolic dissociation was correlated with an increase in phosphorylated pyruvate dehydrogenase (PDH). Importantly, Txnip directly interacts with both PDH kinase and PDH, indicating its involvement in the regulation of PDH activity. Indeed, islets of Wfs1 -/- mice lacking Txnip demonstrated a robust reduction of phosphorylated PDH and a restoration of capabilities of ATP production in response to glucose. Thus, these finding illustrate impaired energy metabolism in beta cells under the chronic stress conditions and suggest that beta cells may possibly become dedifferentiated to adapt to metabolic insufficiency caused by unresolvable stresses. This provides new insights into molecular mechanisms underlying beta cell loss in diabetes related to cellular stresses, such as Wolfram syndrome. Disclosure K. Amo-Shiinoki: None. K. Tanabe: None. M. Hatanaka: None. Y. Tanizawa: None.