title: Development of diabetes in lean Ncb5or-null mice is associated with manifestations of endoplasmic reticulum and oxidative stress in beta cells.
abstract: 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 β-cell dysfunction and loss. Here we examine early cellular and molecular events associated with manifestations of β-cell defects in Ncb5or(-/-) mice. We observe lower islet β-cell content in pancreata at age 4 weeks and prominent ER distention in β-cells by age 5 weeks. Ultrastructural changes progress rapidly in severity from age 5 to 6 weeks, and their frequency rises from 10% of β-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(-/-) β-cells were assessed with isolated islets from mice at age 5 weeks. Expression levels of the stress marker protein Grp78/BiP and of phosphorylated eIF2α 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(-/-) β-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 β-cells and ER and oxidative stress responses.
authors.affiliation: Department of Physical Therapy and Rehabilitation Science, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.forename: Han-Hung
authors.initials: HH
authors.lastname: Huang
authors.forename: Lesya
authors.initials: L
authors.lastname: Novikova
authors.forename: Kevin
authors.initials: K
authors.lastname: Larade
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Jiang
authors.forename: Terri C
authors.initials: TC
authors.lastname: Thayer
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Frontera
authors.forename: Daniel
authors.initials: D
authors.lastname: Aires
authors.forename: Helin
authors.initials: H
authors.lastname: Ding
authors.forename: John
authors.initials: J
authors.lastname: Turk
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
authors.forename: H Franklin
authors.initials: HF
authors.lastname: Bunn
authors.forename: Lisa
authors.initials: L
authors.lastname: Stehno-Bittel
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000496:Alloxan; D000818:Animals; D015153:Blotting, Western; D042966:Cytochrome-B(5) Reductase / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D007515:Islets of Langerhans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010168:Palmitates / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D056811:Unfolded Protein Response
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D005231:Fatty Acids, Unsaturated; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D010168:Palmitates; D017382:Reactive Oxygen Species; D000496:Alloxan; C488723:Ncb5or protein, mouse; D042966:Cytochrome-B(5) Reductase