Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure

Preservation and expansion of beta-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform of carbohydrate response-element binding protein (ChREBP beta) is a nuclear effector of hyperglycemic stress occurring in beta-cells in response to prolonged glucose exposure, high-fat diet, and diabetes. We show that transient positive feedback induction of ChREBP beta is necessary for adaptive beta-cell expansion in response to metabolic challenges. Conversely, chronic excessive beta-cell-specific overexpression of ChREBP beta results in loss of beta-cell identity, apoptosis, loss of beta-cell mass, and diabetes. Furthermore, beta-cell glucolipotoxicity can be prevented by deletion of ChREBP beta. Moreover, ChREBP beta-mediated cell death is mitigated by overexpression of the alternate CHREBP gene product, ChREBP alpha, or by activation of the antioxidant Nrf2 pathway in rodent and human beta-cells. We conclude that ChREBP beta, whether adaptive or maladaptive, is an important determinant of beta-cell fate and a potential target for the preservation of beta-cell mass in diabetes. ChREBP is a glucose-responsive transcription factor, which regulates glucose-mediated proliferation and cell death in pancreatic beta-cells. Here the authors show that the acute feed forward induction of ChREBP beta is required for adaptive beta-cell expansion, that chronic overexpression of ChREBP beta is toxic to beta-cells, and offer mitigation strategies

Automated summary

This study discovered that the hyperactive isoform of Carbohydrate Response-Element Binding Protein (ChREBP beta) is a nuclear effector in beta-cells that responds to hyperglycemic stress caused by prolonged glucose exposure, high-fat diet, and diabetes. The transient positive feedback induction of ChREBP beta is necessary for adaptive beta-cell expansion, while chronic overexpression of ChREBP beta leads to loss of beta-cell identity, apoptosis, and diabetes. Deletion of ChREBP beta can prevent beta-cell glucolipotoxicity.