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Diabetes. 2018 Aug;67(8):1561-1575. doi: 10.2337/db17-0943. Epub 2018 May 15.

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

Author information

1
Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
2
Departments of Oncological Sciences and Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY.
3
Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
4
Division of Endocrinology and Metabolism and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC.
5
Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY.
6
Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY donald.scott@mssm.edu.

Abstract

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.

PMID:
29764859
PMCID:
PMC6054434
DOI:
10.2337/db17-0943
[Indexed for MEDLINE]
Free PMC Article

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