1. Absence of a reductase, NCB5OR, causes insulin-deficient diabetes
- Author
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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), and Harvard Medical School [Boston] (HMS)-Harvard Medical School [Boston] (HMS)
- Subjects
Blood Glucose ,Male ,medicine.medical_treatment ,MESH: Mice, Knockout ,Impaired glucose tolerance ,Mice ,0302 clinical medicine ,Homeostasis ,Insulin ,MESH: Animals ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,Mice, Knockout ,2. Zero hunger ,0303 health sciences ,Glucose tolerance test ,Multidisciplinary ,medicine.diagnostic_test ,MESH: Glucagon ,Biological Sciences ,medicine.anatomical_structure ,MESH: Homeostasis ,Female ,Oxidoreductases ,Cytochrome-B(5) Reductase ,medicine.drug ,medicine.medical_specialty ,MESH: Diabetes Mellitus ,MESH: Glucose Tolerance Test ,Mice, Inbred Strains ,MESH: Insulin ,Biology ,MESH: Mice, Inbred Strains ,Glucagon ,Streptozocin ,Islets of Langerhans ,03 medical and health sciences ,Internal medicine ,Diabetes Mellitus ,medicine ,Animals ,Humans ,MESH: Oxidoreductases ,MESH: Mice ,030304 developmental biology ,MESH: Humans ,MESH: Islets of Langerhans ,Pancreatic islets ,Endoplasmic reticulum ,MESH: Streptozocin ,Glucose Tolerance Test ,Streptozotocin ,medicine.disease ,MESH: Male ,Endocrinology ,MESH: Blood Glucose ,MESH: Cytochrome-B(5) Reductase ,MESH: Female ,030217 neurology & neurosurgery - 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.
- Published
- 2004