Diabetes mellitus is one of the leading causes of morbidity and mortality in the United States. Type 1-diabetes occurs during childhood or adolescence and is characterized by insulitis, an autoimmune destruction of beta-cells within the islets of Langerhans leading to a marked defect in insulin production. The main genetic determinants are immune response genes, although it has been demonstrated that genetic contributors other than those that modulate immunity can significantly impact susceptibility to type 1 diabetes, including gene products that have no obvious relationship to beta-cell structure or function.

Our lab has cloned and partially characterized a novel flavoheme reductase, Ncb5or, which is a single 60 kDa polypeptide consisting of a 130-residue N-terminal domain, homologous to classic microsomal cytochrome b5, joined by a 90-residue hinge region to a 300-residue C-terminal domain, homologous to classic microsomal cytochrome b5 reductase. Ncb5or is a single copy gene that is highly conserved in all animals and subcellular localization experiments demonstrate that NCB5OR is localized in the ER. Ncb5or -/- mice are viable and have normal blood glucose levels, however they exhibit impaired glucose tolerance. Between 4-6 weeks of age these mice demonstrate a progressive loss of beta-cells in pancreatic islets and develop severe hyperglycemia and also display an enhanced sensitivity to the diabetogenic agent streptozotocin. Since NCB5OR is a reducing enzyme localized in the ER we hypothesize that it functions to protect the cell from oxidative stress. Ncb5or likely has a direct impact on beta-cell development and function, since the beta-cell most certainly requires a tightly balanced redox environment.

Ncb5or appears to be of critical importance in the beta-cell and determination of its role may provide insight into the pathogenesis and potential treatment of type 1 diabetes. It is known that oxidant stress is involved in the pathogenesis of insulitis and the ultimate destruction of beta-cells. Since Ncb5or is a novel reductase, this research presents a new potential target for drug design. Natural substrate or end-product mimics may be used to improve beta-cell viability or enhance insulin production. The potential to maintain or balance the redox environment in the beta-cells of cultured islets could potentially be exploited to improve their yield and survival during isolation and post-transplantation, respectively.