All mice were Tam injected at three wks after HFD was started. (A) No difference was observed in body weight (g) between control genotypes and KO mice. Mean ± SEM, controls; n = 17, KO; n = 12. (B) Fasting (4 hr) blood glucose levels were elevated in KO mice at 11, 16 and 20 wks after HFD. Glucose levels were measured by tail bleeding. Mean ± SEM, control genotypes; n = 17, KO; n = 12. (C) KO mice displayed higher blood glucose levels and area under the GTT curve (Δ-AUC) compared to control genotypes during glucose tolerance testing (GTT) after HFD for 25 wks. GTT were performed at multiple time points after HFD in two independent cohorts and representative results are shown. Mice were fasted (4 hr) prior to IP glucose injection (1 g/Kg body weight) and glucose levels were measured by tail bleeding at each time point (0; non-injected, 15, 30, 60, 90 min). control genotypes; n = 17, KO; n = 6. (D) KO mice exhibited decreased serum insulin levels and an increased serum proinsulin/insulin ratio compared to control genotypes. Insulin and proinsulin ELISAs were performed with the serum obtained from mice after fasting (overnight) and re-feeding (4 r) after HFD for 17 wks. control genotypes; n = 8, KO; n = 12. (E) No difference was observed in insulin tolerance tests performed after HFD for 20 wks. Mice were fasted for 4 hr before IP injection of insulin (1.5units/Kg). Glucose levels were measured by tail bleeding at each time point (0; non-injection, 15, 30, 60, 90, 120 min). control genotypes; n = 17, KO; n = 12. (F–I) Total RNA was extracted from islets isolated from mice after HFD for 30 wks. mRNA expression was measured by qRT-PCR. control genotypes; n = 3, KO; n = 3 mice. (F). ß cell-, α cell- and insulin processing genes. (G) PDI family and SERCA genes. (H) UPR genes. (I) Antioxidant response- and cell death- related genes. All data are shown as Mean ± SEM. p<0.05*, p<0.01**, p<0.001***.