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

• Published in: Diabetes (New York, N.Y.) Vol. 67; no. 8; pp. 1561 - 1575
• Main Authors: Kumar, Anil, Katz, Liora S, Schulz, Anna M, Kim, Misung, Honig, Lee B, Li, Lucy, Davenport, Bennett, Homann, Dirk, Garcia-Ocaña, Adolfo, Herman, Mark A, Haynes, Cole M, Chipuk, Jerry E, Scott, Donald K
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.08.2018
• Subjects: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - chemistry; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Cadaver; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation; Glucose - metabolism; Humans; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Islet Studies; Luminescent Proteins - chemistry; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondrial Dynamics; NF-E2-Related Factor 2 - agonists; NF-E2-Related Factor 2 - antagonists & inhibitors; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Organelle Biogenesis; Oxygen Consumption; Protein Subunits - chemistry; Protein Subunits - genetics; Protein Subunits - metabolism; Rats; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; RNA Interference; Tissue Culture Techniques; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db17-0943

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.