| 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. © 2018 by the American Diabetes Association. |
| Keywords: |
genetics; cell proliferation; mouse; animal; cytology; metabolism; animals; mice; nuclear protein; transcription factor; rna interference; cell line, tumor; mice, inbred c57bl; photoprotein; transgenic mouse; c57bl mouse; luminescent proteins; mice, transgenic; transcription factors; nuclear proteins; gene expression regulation; chemistry; recombinant fusion proteins; tumor cell line; rat; insulin; glucose; rats; protein subunit; protein subunits; pancreas islet beta cell; insulin-secreting cells; oxygen consumption; fusion protein; basic helix loop helix leucine zipper transcription factor; basic helix-loop-helix leucine zipper transcription factors; tissue culture technique; tissue culture techniques; cadaver; agonists; transcription factor nrf2; humans; human; mitochondrial dynamics; secretion (process); antagonists and inhibitors; organelle biogenesis; mlxipl protein, human; mlxipl protein, mouse; nfe2l2 protein, human; nfe2l2 protein, mouse; nf-e2-related factor 2
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