In model Ins2+/Akita β-cells/islets, the anomalies we characterize represent the extensive defects that arise from PIHO disorder and are known to be associated with diabetes, including insulin deficiency, GSIS impairment, organelle structure abnormality, oxidative and ER stress, decelerated cell proliferation, increased cell death, disproportionally high proinsulin/insulin ratio [32], and insulin resistance [53]. Here, INS is linked to diabetes mellitus.