Beta Cell Stress and Inflammation Linked to Beta Cell Death

When mis-shaped proteins accumulate in the cells protein production machinery it creates stress within the cells normal protein production processes. If the stress is unresolved, the cell will be rendered dysfunctional and will die. Beta cells are specialized cells that produce and secrete large amounts of proteins including insulin and are therefore uniquely sensitive to this type of stress. It has long been thought that this type of stress was responsible for the beta cell dysfunction and death that occurs in T1D and T2D, but links between beta cell stress, inflammation and cell death in diabetes remained elusive. In simultaneously published reports, Dr. Feroz Papa and Dr. Fumihiko Urano independently linked stress in beta cells to activation of an inflammatory pathway and cell death through a protein called TXNIP, known to be associated with cell death. Furthermore, the groups demonstrated that inhibiting the pathway reduced inflammation and cell death and protected against beta cell loss in a mouse model of diabetes. Together, these findings suggest that targeting this stress pathway or the TXNIP protein could be a beneficial therapeutic approach for promoting beta cell health and survival in T1D.

References:

Lerner, AG., Upton, J., Praveen, PVK. et al. (2012). IRE1± Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER Stress. Cell Metab 16, 250-264. Oslowski, CM., Hara, T., O’Sullivan-Murphy, B. et al. (2012). Thioredoxin-Interacting Protein Mediates ER Stress-Induced ² Cell Death through Initiation of the Inflammasome. Cell Metab 16, 265-273.

Investigators and Institutions:

This work was led by Dr. Feroz Papa at UCSF and Dr. Fumihiko Urano at Washington University School of Medicine.

Ramifications for Individuals with Type 1 Diabetes:

This research identifies a potential drug development target to reduce stress and increase survival of beta cells to delay or prevent T1D. Further work is required to identify drug-like compounds that can target the pathway and demonstrate that they are safe and effective in animal models before moving to human studies.

JDRF Involvement:

Work in Dr. Uranos laboratory was funded, in part, by JDRF. A previous JDRF grant to Dr. Papa supported the development of tools and reagents necessary for the present study.