Trx2^ADKO mice develop T2DM-related end-organ damage. (A–E) Trx2-KO mice exhibit decreased insulin content and increased β cell apoptosis. (A) Representative hematoxylin and eosin–stained pancreas sections showing pancreatic islets of WT and Trx2^ADKO mice at the indicated ages. Scale bars, 20 µm. (B) Nuclei density of six randomly selected pancreatic islets (n = 6 mice). (C) Detection of β cell apoptosis by costaining of TUNEL (green) and insulin (red). Representative images from WT and Trx2^ADKO mice at the indicated ages. Scale bars, 20 µm. (D) Quantification of TUNEL-positive β cells (right panel; n = 6 mice). (E) Representative transmission electron micrographs of pancreas tissue from WT and Trx2 ^ADKO mice (three images/mouse, n = 3 mice/group). Squares correspond to the magnified areas (bottom panel). Scale bars, 1 µm. M, mitochondria. Arrowheads indicate empty granules. (F) Quantification of insulin granules per µm² islet. (G) Representative transmission electron micrographs of kidney tissue from WT and Trx2^ADKO mice (n = 3). White squares correspond to the magnified areas (bottom panel). Red arrowhead indicates podocyte foot process fusion. Scale bars, 1 µm. (H–L) Quantitative analysis of de novo lipogenesis and hepatic gluconeogenic genes. (H) Relative mRNA expression of lipogenesis genes in liver in 14-wk-old male WT and Trx2^ADKO mice (n = 6). (I and J) Relative mRNA expression of hepatic gluconeogenic genes in liver of 14-wk-old male WT and Trx2^ADKO mice (n = 8). (K) Relative mRNA expression of the indicated de novo lipogenesis genes in eWAT of 14-wk-old male WT and Trx2^ADKO mice (n = 8). (L) Relative mRNA expression of lipolysis genes in eWAT in 14-wk-old male WT and Trx2^ADKO mice (n = 6). Quantitative data represent the mean ± SEM. ns, not significant; **, P < 0.01; ***, P < 0.001 compared with WT controls (two-tailed Student’s t test). Acc, acetyl-CoA carboxylase 1; Atgl, adipose TG lipase; Fasn, fatty acid synthase; G6p, glucose 6-phosphatase; Gck, glucokinase; Gys2, glycogen synthase 2; Hsl, hormone-sensitive lipase; Lpl, lipoprotein lipase; Pc, pyruvate carboxylase. (M–P) TEM analysis of brown adipose mitochondria. (M) Representative transmission electron micrographs of interscapular BAT (iBAT) sections from WT and Trx2^ADKO mice at the indicated ages. Asterisks indicate LDs. Squares correspond to the magnified areas (bottom panel). Arrowheads indicate mitochondria. Scale bars, 0.5 µm. (N–P) Number of mitochondria, number of damaged mitochondria, and cristae surface area/outer membrane (OM) surface area (six images/mouse; n = 3 mice/group). Quantitative data represent the mean ± SEM. ns, not significant; *, P < 0.05; **, P < 0.01; ***, P < 0.001 versus WT (two-tailed Student’s t test). w, weeks.