KO islets accumulate oxidative stress, inflammation, and fibrosis.

(A) mRNA-Seq expression values for 25/368 of the mRNAs identified by Venn analysis (Fig 3C; right panel, underlined) that are reduced by Ire1α because of glucose that accumulates in the KO^{Fe/-; Cre} ([n = 5], [p-values ≤ 0.05]). (B) Oxidized lipid (hydroxyl-octadecadienoic acids, HODEs) from islets of the indicated genotypes infected with Ad-Cre Ad-GFP or no virus control ([n = 2; controls versus n = 3; Ad-Cre], [p = 0.00434]). (C) Antinitrotyrosine immunohistochemistry (IHC) of islets from 8-mo-old WT^Fe/Fe and KO^{Fe/Fe; Cre} mice 15 wk post-Tam with or without BHA diet for 3 wk. (Scale bar, 50 μm) (WT^Fe/Fe [n = 4 with BHA], [n = 5 regular chow]), (KO^{Fe/Fe; Cre} [n = 5 with BHA], [n = 6 regular chow]). (p = 0.00698; WT^Fe/Fe versus WT^Fe/Fe with BHA), (p = 0.04018; WT^Fe/Fe versus KO^{Fe/Fe; Cre}) and (p = 0.04420; KO^{Fe/Fe; Cre} versus KO^{Fe/Fe; Cre} with BHA). (D) Masson’s trichrome stain (blue) for collagens. Results demonstrate increased staining surrounding KO^{Fe/Fe; Cre} islets with haemotoxylin (red) and eosin (black) co-stains. Quantification of percent strong collagen stain is shown below the images. Scale bar, 50 μm. (WT^Fe/Fe [n = 4 with BHA], [n = 5 regular chow]), (KO^{Fe/Fe; Cre} [n = 5 with BHA], [n = 6 without BHA]). Percent strong collagen stain significance for WT^Fe/Fe without BHA versus KO^{Fe/Fe; Cre} without BHA p = 0.01049). (E) 8-mo-old male mice carrying the doubly floxed allele (Ire1α^Fe/Fe) with and without RIP-Cre 12 wk post-Tam had their pre-BHA GTTs taken, and then half were fed the antioxidant BHA supplemented chow diet for 3 wk or not before examining the mice by GTT again. (WT^Fe/Fe [n = 11 with BHA], [n = 12 regular chow], [p = 0.035]), (KO^{Fe/Fe; Cre} [n = 18 with BHA], [n = 16 without BHA], [p = 0.041]). P-values were calculated by one-tailed student’s t test comparison of the areas under the GTT curves for the biological replicates of control group WT^Fe/Fe versus the Tam-induced KO^{Fe/Fe; Cre} group.