INS and type 2 diabetes mellitus: In this study, we have exploited several independent lines of evidence to establish the presence of aberrant disulfide-linked proinsulin complexes in the β-cells of human islets and model systems, in states that alter the ER folding environment, and in T2D progression prior to onset of β-cell dedifferentiation (Bensellam et al., 2018) or death (Eizirik and Millard, 2014; Kanekura et al., 2015; Marchetti et al., 2012; Papa, 2012).