Beta-cell injury in Ncb5or-null mice is exacerbated by consumption of a high-fat diet

NADH-cytochrome b5 oxidoreductase (Ncb5or) in endoplasmic reticulum (ER) is involved in fatty acid metabolism, and Ncb5or-/- mice fed standard chow (SC) are insulin-sensitive but weigh less than wild-type (WT) littermates. Ncb5or-/- mice develop hyperglycemia at about age 7 wk due to beta-cell dysfunction and loss in association with saturated fatty acid (SFA) accumulation and manifestations of ER and oxidative stress. Here we report that when Ncb5or-/- mice born to heterozygous mothers fed a high fat (HF) diet continue to ingest HF, they weigh as much as SC-fed WT at age 5 wk. By age 7 wk, diabetes mellitus develops in all HF-fed versus 68% of SC-fed Ncb5or-/- mice. Islet beta-cell content in age 5-wk Ncb5or-/- mice fed HF for 7 days is lower (53%) than for those fed SC (63%), and both are lower than for WT (75%, SC, vs. 69%, HF). Islet transcript levels for markers of mitochondrial biogenesis (PGC-1a) and ER stress (ATF6a) are higher in Ncb5or-/- than WT mice but not significantly affected by diet. Consuming a HF diet exacerbates Ncb5or-/- beta-cell accumulation of intracellular SFA and increases the frequency of ER distention from 11% (SC) to 47% (HF), thus accelerates beta-cell injury in Ncb5or-/- mice.