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

Journal Article (Journal Article)

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

Full Text

Duke Authors

Cited Authors

  • Katz, LS; Brill, G; Zhang, P; Kumar, A; Baumel-Alterzon, S; Honig, LB; Gómez-Banoy, N; Karakose, E; Tanase, M; Doridot, L; Alvarsson, A; Davenport, B; Wang, P; Lambertini, L; Stanley, SA; Homann, D; Stewart, AF; Lo, JC; Herman, MA; Garcia-Ocaña, A; Scott, DK

Published Date

  • July 30, 2022

Published In

Volume / Issue

  • 13 / 1

Start / End Page

  • 4423 -

PubMed ID

  • 35908073

Pubmed Central ID

  • PMC9339008

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-022-32162-x

Language

  • eng

Conference Location

  • England