Absence of a reductase, NCB5OR, causes insulin-deficient diabetes.
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.
Xie
Jianxin
J
Hematology Division, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Zhu
Hao
H
Larade
Kevin
K
Ladoux
Annie
A
Seguritan
Ayden
A
Chu
Michelle
M
Ito
Susumu
S
Bronson
Roderick T
RT
Leiter
Edward H
EH
Zhang
Chen-Yu
CY
Rosen
Evan D
ED
Bunn
H Franklin
HF
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
D001786:Blood Glucose; D007328:Insulin; D013311:Streptozocin; D005934:Glucagon; D010088:Oxidoreductases; C488723:Ncb5or protein, mouse; D042966:Cytochrome-B(5) Reductase