Activation of Nrf2 Is Required for Normal and ChREBPα-Augmented Glucose-Stimulated β-Cell Proliferation.

Published

Journal Article

Patients with both major forms of diabetes would benefit from therapies that increase β-cell mass. Glucose, a natural mitogen, drives adaptive expansion of β-cell mass by promoting β-cell proliferation. We previously demonstrated that a carbohydrate response element-binding protein (ChREBPα) is required for glucose-stimulated β-cell proliferation and that overexpression of ChREBPα amplifies the proliferative effect of glucose. Here we found that ChREBPα reprogrammed anabolic metabolism to promote proliferation. ChREBPα increased mitochondrial biogenesis, oxygen consumption rates, and ATP production. Proliferation augmentation by ChREBPα required the presence of ChREBPβ. ChREBPα increased the expression and activity of Nrf2, initiating antioxidant and mitochondrial biogenic programs. The induction of Nrf2 was required for ChREBPα-mediated mitochondrial biogenesis and for glucose-stimulated and ChREBPα-augmented β-cell proliferation. Overexpression of Nrf2 was sufficient to drive human β-cell proliferation in vitro; this confirms the importance of this pathway. Our results reveal a novel pathway necessary for β-cell proliferation that may be exploited for therapeutic β-cell regeneration.

Full Text

Duke Authors

Cited Authors

  • Kumar, A; Katz, LS; Schulz, AM; Kim, M; Honig, LB; Li, L; Davenport, B; Homann, D; Garcia-Ocaña, A; Herman, MA; Haynes, CM; Chipuk, JE; Scott, DK

Published Date

  • August 2018

Published In

Volume / Issue

  • 67 / 8

Start / End Page

  • 1561 - 1575

PubMed ID

  • 29764859

Pubmed Central ID

  • 29764859

Electronic International Standard Serial Number (EISSN)

  • 1939-327X

Digital Object Identifier (DOI)

  • 10.2337/db17-0943

Language

  • eng

Conference Location

  • United States