Figure 1.

Molecular pathways and therapeutic targets for beta cell unfolded protein response (UPR)-mediated apoptosis and senescence in type 1 diabetes (T1D). (A) Beta cell apoptosis in T1D results from persistent endoplasmic reticulum (ER) stress that leads to activation of UPR master regulators IRE1α, PERK and ATF6. IRE1α mediates its functions through its RNAse and kinase activities that are potentiated by the Abelson tyrosine-protein kinase (ABLs). The balance of each UPR regulator dictates the outcome on beta cell fate. Unrelieved ER stress signals through IRE1α and PERK and shifts the pathway towards a terminal UPR and apoptosis mediated by thioredoxin interacting protein (TXNIP), whereas ATF6 is the major mediator of adaptive UPR leading to beta cell survival. Clinical trials in new onset adult T1D patients have used Verapamil, Imatinib or tauroursodeoxycholic acid (TUDCA) to attenuate terminal UPR and apoptosis and/or enhance adaptive UPR to delay the decline in residual beta cell function. (B) Beta cell senescence in T1D may be initiated by unresolved DNA damage (although the precise triggers of DNA damage remain unknown). A persistent DNA damage response (DDR) in beta cells is indicated by gH2A.X which is mediated by ATM. DNA damaged beta cells show activation of cyclin-dependent kinase inhibitors p21 and p16, which enforce a senescent growth arrest. Senescent beta cells upregulate the antiapoptotic protein Bcl-2 and develop a senescence-associated secretory phenotype (SASP). Small molecule inhibitors including senolytic compounds targeting Bcl-2 (ABT-199, ABT-737) or suppressing SASP at the level of gene expression (iBET-762) mitigate the deleterious effects of accumulated senescent beta cells in NOD mice and prevent T1D. These drugs have not been tested in clinical trials for T1D. The white circles and the β symbol indicate the nucleus, while the purple structure is the ER and black dots indicate insulin granules.