title: Absence of a reductase, NCB5OR, causes insulin-deficient diabetes.
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.
authors.affiliation: Hematology Division, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Xie
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
authors.forename: Kevin
authors.initials: K
authors.lastname: Larade
authors.forename: Annie
authors.initials: A
authors.lastname: Ladoux
authors.forename: Ayden
authors.initials: A
authors.lastname: Seguritan
authors.forename: Michelle
authors.initials: M
authors.lastname: Chu
authors.forename: Susumu
authors.initials: S
authors.lastname: Ito
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Edward H
authors.initials: EH
authors.lastname: Leiter
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Zhang
authors.forename: Evan D
authors.initials: ED
authors.lastname: Rosen
authors.forename: H Franklin
authors.initials: HF
authors.lastname: Bunn
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D042966:Cytochrome-B(5) Reductase / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005934:Glucagon / Q000378:metabolism; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin / Q000008:administration & dosage
chemical_list: D001786:Blood Glucose; D007328:Insulin; D013311:Streptozocin; D005934:Glucagon; D010088:Oxidoreductases; C488723:Ncb5or protein, mouse; D042966:Cytochrome-B(5) Reductase