| First Author | Wang W | Year | 2011 |
| Journal | Biochim Biophys Acta | Volume | 1812 |
| Issue | 11 | Pages | 1532-41 |
| PubMed ID | 21839170 | Mgi Jnum | J:180337 |
| Mgi Id | MGI:5306112 | Doi | 10.1016/j.bbadis.2011.07.016 |
| Citation | Wang W, et al. (2011) Development of diabetes in lean Ncb5or-null mice is associated with manifestations of endoplasmic reticulum and oxidative stress in beta cells. Biochim Biophys Acta 1812(11):1532-41 |
| abstractText | NADH-cytochrome b5 oxidoreductase (Ncb5or) is an endoplasmic reticulum (ER)-associated redox enzyme involved in fatty acid metabolism, and phenotypic abnormalities of Ncb5or(-/-) mice include diabetes and lipoatrophy. These mice are lean and insulin-sensitive but become hyperglycemic at age 7 weeks as a result of beta-cell dysfunction and loss. Here we examine early cellular and molecular events associated with manifestations of beta-cell defects in Ncb5or(-/-) mice. We observe lower islet beta-cell content in pancreata at age 4 weeks and prominent ER distention in beta-cells by age 5 weeks. Ultrastructural changes progress rapidly in severity from age 5 to 6 weeks, and their frequency rises from 10% of beta-cells at 5 weeks to 33% at 6 weeks. These changes correlate temporally with the onset of diabetes. ER stress responses and lipid load in Ncb5or(-/-) beta-cells were assessed with isolated islets from mice at age 5 weeks. Expression levels of the stress marker protein Grp78/BiP and of phosphorylated eIF2alpha protein were found to be reduced, although their transcript levels did not decline. This pattern stands in contrast to the canonical unfolded protein response. Ncb5or(-/-) beta-cells also accumulated higher intracellular levels of palmitate and other free fatty acids and exhibited greater reactive oxygen species production than wild-type cells. An alloxan-susceptible genetic background was found to confer accelerated onset of diabetes in Ncb5or(-/-) mice. These findings provide the first direct evidence that manifestations of diabetes in lean Ncb5or(-/-) mice involve saturated free fatty acid overload of beta-cells and ER and oxidative stress responses. |
