GRP94 konck down (KD) or knockout (KO) β cells were more susceptible to apoptosis through the IGF-1R/AKT/Bim axis in vitro when stimulated with stress factors, or in vivo when insulin+ β cell-specific GRP94 conditional KO mice were challenged with high fat diet (HFD) to mimic diabetogenic conditions associated with T2D. Here, INS is linked to type 2 diabetes mellitus.