However, in the absence of INS gene mutations, it has not been established the extent to which proinsulin misfolding is present in the early triggering stages of T2D, including prediabetes and mild dysglycemia — prior to more obvious islet failure including β-cell degranulation and dedifferentiation (Accili et al., 2016; Kahn, 1998; Kahn et al., 2009) that occurs in both human islets (Cinti et al., 2016) and rodent islets (Ishida et al., 2017). This evidence concerns the gene INS and prediabetes syndrome.