Endocrine Abstracts

Accumulated knowledge in the last five years suggests that components of the unfolded protein response (UPR) in the endoplasmic reticulum (ER) play a dual role in pancreatic beta cells, acting as regulators under physiological conditions or as triggers of beta cell dysfunction and death under situations of chronic and/or severe ER stress. These observations indicate that the large capacity of beta cells to synthesize, sort and secrete insulin may also make them vulnerable to chronic exposure to high glucose or free fatty acids, agents that contribute to beta cell dysfunction and apoptosis in type 2 diabetes. Beta cell ER stress is also present in the context of type 1 diabetes, but following different pathways. Thus, the cytokines IL-1β and IFN-γ trigger a severe ER stress by respectively inducing an NO-mediated depletion of ER calcium and inhibiting ER chaperones, thus hampering beta cell defenses. This results in amplification of the pro-apoptotic pathways and eventually beta cell death.

Some of the key issues that remain to be clarified in this novel field are: a. the transition from physiology to pathology, i.e. how the physiological UPR evolves to severe ER stress and, in some cases, beta cell death; b. the mechanism utilized by beta cells to recover from ER stress; c. the ‘point of no return’ for beta cell apoptosis, and the nature of the pro-apoptotic signals generated by ER stress.