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Absence of a reductase, NCB5OR, causes insulin-deficient diabetes

Authors :
Evan D. Rosen
Jianxin Xie
Chen-Yu Zhang
Annie Ladoux
Hao Zhu
Susumu Ito
Edward H. Leiter
Michelle Chu
H. Franklin Bunn
Kevin Larade
Ayden Seguritan
Roderick T. Bronson
Hematology Div, Birgham and Womens Hospital Boston
Brigham and Women's Hospital [Boston]
Institut de signalisation, biologie du développement et cancer (ISBDC)
Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS)
COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)
Cell Biology Harvard Medical School Boston
Harvard Medical School [Boston] (HMS)
Dept Pathology Harvard Med School Boston
The Jackson Laboratory [Bar Harbor] (JAX)
Beath Israel Deaconess Med Center Boston
Beth Israel Deaconess Medical Center [Boston] (BIDMC)
Harvard Medical School [Boston] (HMS)-Harvard Medical School [Boston] (HMS)
Source :
Proceedings of the National Academy of Sciences of the United States of America, Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2004, 101 (29), pp.10750-5. ⟨10.1073/pnas.0404044101⟩
Publication Year :
2004
Publisher :
Proceedings of the National Academy of Sciences, 2004.

Abstract

NCB5OR is a highly conserved NAD(P)H reductase that contains a cytochrome b5-like domain at the N terminus and a cytochrome b5 reductase-like domain at the C terminus. The enzyme is located in the endoplasmic reticulum (ER) and is widely expressed in organs and tissues. Targeted inactivation of this gene in mice has no impact on embryonic or fetal viability. At 4 weeks of age, Ncb5or -/- mice have normal blood glucose levels but impaired glucose tolerance. Isolated Ncb5or -/- islets have markedly impaired glucose- or arginine-stimulated insulin secretion. By 7 weeks of age, these mice develop severe hyperglycemia with markedly decreased serum insulin levels and nearly normal insulin tolerance. As the animals age, there is a progressive loss of beta cells in pancreatic islets, but there is no loss of alpha, delta, or PP cells. Electron microscopy reveals degranulation of beta cells and hypertrophic and hyperplastic mitochondria, some of which contain electron dense inclusions. Four-week-old Ncb5or -/- mice have enhanced sensitivity to the diabetogenic agent streptozotocin. NCB5OR appears to play a critical role in protecting pancreatic beta cells against oxidant stress.

Details

ISSN :
10916490 and 00278424
Volume :
101
Database :
OpenAIRE
Journal :
Proceedings of the National Academy of Sciences
Accession number :
edsair.doi.dedup.....fe5d54e658c42bf0f4870636043ce20e