Perk gene dosage modulates diabetic progression of the Akita mouse. A–E: Four Perk genotypes, including Perk+/+ (“2”), Perk+/− (“1”), βPerk;Perk+/+ (“β2”), and βPerk;Perk+/− (“β1”), were crossed to Ins2+/Akita mice to assess glucose homeostasis and insulin in the resulting strains. The expression of Perk mRNA is elevated ∼80% above normal in βPerk;Perk+/+ in β-cells. A: Progression toward overt diabetes in Ins2+/Akita mutant is positively correlated with increasing Perk gene dosage. Blood glucose was measured at P23 and P28 in the same group of mice (β2: n = 11, β1: n = 11, 2: n = 45, 1: n = 42; *P < 0.05, **P < 0.005, ****P < 0.00005, *******P < 0.00000005). B: Random blood glucose levels measured in P17 and P23 Ins2Akita/Akita mutant mice show that higher blood glucose levels are associated with an increase in Perk gene dosage (2: n = 6, 1: n = 10; *P < 0.05). C: Pancreatic insulin content decreases with increasing Perk gene dosage in the Ins2+/Akita mice. The insulin content of Perk wild-type and heterozygous mice with the βPerk transgene (β1 and β2) were pooled (n = 12) and compared with mice without the βPerk transgene (1 and 2) (n = 12) and found to be significantly different (*P = 0.03). D: Pancreatic insulin content decreases with increasing Perk gene dosage in the Ins2+/+ mice (β1 and β2, n = 10; 1 and 2, n = 8). The difference between mice with and without βPerk transgene is statistically significant (*P = 0.02). E: An increase in Perk gene dosage was found to lead to an ablation of in vivo GSIS in P28 Ins2+/+ mice (β1 and β2: n = 12, 1 and 2: n = 11; **P < 0.005). P28 Ins2+/Akita littermates demonstrated lower fasting serum insulin levels and impaired GSIS independent of Perk gene dosage (β1 and β2: n = 11, 1 and 2: n = 10).