Scientists created mice lacking the ER chaperone GRP78 specifically in pancreatic beta cells. Without GRP78, the pups developed acute insulin-deficient diabetes before weaning, alongside a drop in beta cell mass driven by increased apoptosis.
Biology2 weeks ago
Unfolded-protein stress kills insulin cells via JNK and p53 in mice and humans
Blocking JNK and p53 helped protect pancreatic beta cells in two mouse models of ER stress and in human cells.
How ER stress triggers death
GRP78 deletion in pancreatic beta cells caused acute insulin-deficient diabetes in pups before weaning, with reduced beta cell mass due to increased apoptosis. Molecular analyses pointed to deregulated unfolded-protein response signaling, with IRE1 activity driving the cell death. Researchers identified a JNK–p53 pathway downstream of IRE1 kinase as a key mediator of beta cell death during UPR activation. In two distinct ER-stress diabetes models, inhibiting JNK in vivo protected against beta cell death. In human beta cells, pharmacological inhibition of both JNK and p53 improved cell survival during GRP78 knockdown–induced UPR.
Potential targets for protection
Because ER stress is linked to beta cell loss in both type 1 and type 2 diabetes, the findings help map a more specific chain of events that leads from unfolded-protein stress to beta cell death. The work also points to JNK and p53 as targets that could, in principle, help preserve insulin-producing cells during ER stress.
Evidence and caveats
The evidence includes genetically engineered mouse experiments, molecular pathway analyses showing where signals connect, in vivo protection from beta cell death using JNK inhibition in two ER-stress diabetes models, and pharmacological testing in human beta cells. Limitations include that the results described are based on the specific GRP78 loss and GRP78 knockdown settings used in the study, and the abstract does not provide details on effect sizes, sample sizes, or how closely these models match every aspect of human diabetes.
// Source
Journal of Clinical Investigation · 2026 · DOI: 10.1172/jci193035
Authors: Rohit B. Sharma, CHRISTINE DARKO, Ying Wang, THALIA A. CASTRO, Tara Doma Lama, Brian Gablaski, Andrew Rappa, David Redmond, Jason K. Kim, Amy S. Lee, Laura Alonso
Institutions: Cornell University, University of Southern California, University of Massachusetts Chan Medical School, UMass Memorial Medical Center
