We find that, beyond the islet cell heterogeneity appearing in the islets of β-Hrd1-KO mice that consistently develop hypoinsulinemic diabetes, there is a notable increase in the phosphorylation state of eIF2α, which is known to limit proinsulin biosynthesis, as well as an activation of autophagy that participates in proinsulin turnover. The gene discussed is EIF2A; the disease is diabetes mellitus.