Fig. 1: Protein-Protein Interaction between 14-3-3 and ChREBPα regulates β-cell fate.

a. Under normoglycemic conditions, ChREBPα remains mostly cytoplasmic by binding to 14-3-3. ChREBPα is one of very few phosphorylation-independent 14-3-3 partner proteins and binds via a pocket containing a phosphate or sulfate ion, ketone, or AMP. b. In acute hyperglycemia, ChREBPα dissociates from 14-3-3 and transiently translocates into the nucleus where it binds multiple ChoREs and promotes adaptive β-cell expansion. c. In prolonged hyperglycemia or hyperglycemia combined with hyperlipidemia (glucolipotoxicity), ChREBPα initiates and maintains a feed-forward surge in ChREBPβ expression, leading to β-cell demise. d. Novel class of molecular glue drugs specifically stabilize ChREBPα/14-3-3 interaction, prevent surge of ChREBPβ expression in glucolipotoxicity, and protect β-cell identity and survival.