The role of Fas-mediated apoptotic pathway in amyloid-induced beta-cell death

In type 2 diabetes (T2D), progressive dysfunction and loss of beta-cells in pancreatic islets eventually leads to hyperglycemia. The formation of toxic protein aggregates known as islet amyloid contributes to beta-cell dysfunction and death in T2D. Islet amyloid is formed mainly by aggregation of the beta-cell hormone named islet amyloid polypeptide (IAPP), which is produced and released along with insulin. Amyloid also forms in cultured and transplanted human islets, indicating that in addition to its role in pathogenesis of T2D, amyloid formation contributes to islet graft failure in type 1 diabetes (T1D). The mechanism(s) underlying amyloid-induced beta-cell death are still unclear. Fas is a cell death receptor that has been implicated in the pathogenesis of both T1D and T2D. We hypothesised that amyloid-induced beta-cell death is mediated, at least partially, by activation of the Fas apoptotic pathway and that blocking the key steps in this pathway may protect beta-cells from amyloid toxicity in T2D and islet grafts in T1D. Our studies showed that endogenously formed human IAPP aggregates induce beta-cell Fas upregulation leading to interaction of Fas and its ligand FasL, thereby promoting activation of the Fas apoptotic pathway initiated by caspase-8. Blocking Fas/FasL interaction reduced amyloid-induced beta-cell apoptosis, and beta-cell specific deletion of Fas or caspase-8 in hIAPP-expressing mouse islets improved beta-cell survival and function. We further demonstrated that amyloid-induced beta-cell Fas upregulation is mediated by interleukin-1beta (IL-1beta). Amyloid formation in cultured islets closely correlated with elevated IL-1beta production and blocking IL-1beta signalling reduced amyloid-induced beta-cell Fas upregulation, caspase-8 activation and apoptosis. Moreover, IL-1beta-induced beta-cell dysfunction caused impaired prohIAPP processing and potentiated amyloid formation, which was restored by blocking IL-1 receptor. These findings support a dual role for IL-1beta in amyloid formation and its beta-cell toxicity. Similarly, enhancing islet function by the GLP-1 receptor agonist exenatide improved impaired prohIAPP processing and reduced amyloid formation. In summary, our data show that the Fas apoptotic pathway plays a major role in amyloid-induced beta-cell death and that blocking the key mediators of this pathway may provide a new therapeutic strategy to preserve beta-cells in T2D and prolong islet graft survival in T1D.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat