INS and diabetes mellitus: Although the β-HRD1–KO mice develop diabetes with abnormally small insulin secretory granules (Figures 1 and 4, and Supplemental Figure 5), the increase of phospho-eIF2α (Figure 5, A and B) seems unlikely to simply reflect elevated extracellular glucose (62) because it also occurs upon acute β cell HRD1 inhibition under conditions in which glucose is invariant (Figure 6, B and C, and Supplemental Figure 9), as well as in human islets (Supplemental Figure 8).