This phenomenon has been studied extensively in the Akita mouse model of diabetes, which carries a proinsulin cysteine disruption mutation (C96Y) that leads to mutant proinsulin accumulation in the ER, enlarged ER, reduction of secretory granules and mitochondrial swelling (Izumi et al., 2003; Kayo and Koizumi, 1998; Wang et al., 1999; Yoshioka et al., 1997; Zuber et al., 2004). Here, INS is linked to diabetes mellitus.