It is indisputable that ß-cell ER stress can be triggered by proinsulin misfolding in the setting of INS gene coding sequence mutations (Liu et al., 2018) but there are also strong reasons to think that even in the absence of INS gene mutations, proinsulin misfolding could be an early feature in the progression of T2D (Arunagiri et al., 2018; Riahi et al., 2018; Scheuner and Kaufman, 2008). Here, INS is linked to type 2 diabetes mellitus.