The most convenient and direct evidence is pancreas-specific Manf−/− mice developed severe insulin-dependent diabetes due to progressive reduction of β cell mass and activation of UPR, including spliced Xbp1 and Chop mRNA, which implicates that MANF deficiency may lead to activation of the UPR following unresolved ER stress [32]. Here, MANF is linked to type 1 diabetes mellitus.