@article{b0e2661e2b6142fd9221cb5158bb4046,
title = "Activation of Nrf2 is required for normal and ChREBPA-augmented glucose-stimulated B-cell proliferation",
abstract = "Patients with both major forms of diabetes would benefit from therapies that increase b-cell mass. Glucose, a natural mitogen, drives adaptive expansion of b-cell mass by promoting b-cell proliferation. We previously demonstrated that a carbohydrate response element-binding protein (ChREBPa) is required for glucose-stimulated b-cell proliferation and that overexpression of ChREBPa amplifies the proliferative effect of glucose. Here we found that ChREBPa reprogrammed anabolic metabolism to promote proliferation. ChREBPa increased mitochondrial biogenesis, oxygen consumption rates, and ATP production. Proliferation augmentation by ChREBPa required the presence of ChREBPb. ChREBPa increased the expression and activity of Nrf2, initiating antioxidant and mitochondrial biogenic programs. The induction of Nrf2 was required for ChREBPa-mediated mitochondrial biogenesis and for glucose-stimulated and ChREBPa-augmented b-cell proliferation. Overexpression of Nrf2 was sufficient to drive human b-cell proliferation in vitro; this confirms the importance of this pathway. Our results reveal a novel pathway necessary for b-cell proliferation that may be exploited for therapeutic b-cell regeneration.",
author = "Anil Kumar and Katz, {Liora S.} and Schulz, {Anna M.} and Misung Kim and Honig, {Lee B.} and Lucy Li and Bennett Davenport and Dirk Homann and Adolfo Garcia-Oca{\~n}a and Herman, {Mark A.} and Haynes, {Cole M.} and Chipuk, {Jerry E.} and Scott, {Donald K.}",
note = "Funding Information: Acknowledgments. The authors thank Dr. Howard Towle (University of Minnesota) for the ChREBPa-expressing adenovirus and Dr. Chris Newgard (Stedman Nutrition and Metabolism Center, Duke University) for providing INS1-derived 832/13 cells and for helpful discussions. The authors thank Dr. Andrew Stewart (Icahn School of Medicine at Mount Sinai, New York, NY) for helpful discussions and Gabrielle Brill (Icahn School of Medicine at Mount Sinai, New York, NY) for providing technical assistance. The authors also thank the Icahn School of Medicine at Mount Sinai Microscopy Core, the Albert Einstein School of Medicine Stable Isotope & Metabolomics Core, and the Einstein/Sinai Diabetes Center Human Islet and Adenovirus Core. Funding. This work was supported by Deutsche Forschungsgemeinschaft (grant no. DFG SCHU 3023/1-1 to A.M.S.), the National Institute of Diabetes and Digestive and Kidney Diseases (grant nos. T32 DK007516 to M.K., P30 DK020541-38 to A.G.-O., R01 DK100425 to M.A.H., and R01 DK065149 and R01 DK108905 to D.K.S.), the National Institute on Aging (grant no. R01 AG047182 to C.M.H.), the National Cancer Institute (grant no. R01 CA206005 to J.E.C.), the National Institute of Allergy and Infectious Diseases (grant no. RO1 AI093637 to D.H.), the American Diabetes Association (grant nos. ADA 7-11-BS-128 and ADA 1-17-IBS-116 to D.K.S.), and JDRF (grant no. SRF 17-2011-598 to D.K.S.). J.E.C. has received an American Cancer Society Research Scholar Award. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Publisher Copyright: {\textcopyright} 2018 by the American Diabetes Association.",
year = "2018",
month = aug,
day = "1",
doi = "10.2337/db17-0943",
language = "English",
volume = "67",
pages = "1561--1575",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "8",
}