ERN1 and diabetes mellitus: In agreement, deficient WFS1 expression in mice and human led to hyperactivation of the ATF6α pathway, and subsequent increased activation of the ATF4, CHOP and IRE1α/XBP1 pathways inducing beta cell dysfunction and apoptosis resulting in diabetes (Ishihara et al., 2004; Riggs et al., 2005; Yamada et al., 2006; Fonseca et al., 2010; Shang et al., 2014).