Increased vulnerability of newly forming beta cells to cytokine-induced cell death

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Abstract
Aims/hypothesis Beta cell destruction in type 1 diabetes is apparently mediated by the release of cytokines. We questioned whether cytokine-induced apoptosis preferentially kills replicating beta cells. Materials and methods In the first experiment, rat insulinoma (RIN) cells were studied for 36 h by time-lapse video microscopy. Cells were exposed to three doses of a cytokine mixture (maximal concentration: IL-1β 50 U/ml; TNF-α 1,000 U/ml; IFN-γ 1,000 U/ml) or vehicle and analysed for the total cell number (2-h intervals) and timing of each cell death and division. In the second experiment, isolated human islets were incubated with the same cytokine mixture for 24 h and examined for replication and paired (postmitotic) apoptosis. Results In the first experiment, after application of cytokines, apoptosis occurred most frequently immediately after the next or subsequent cell mitosis (pp<0.001). Conclusions/interpretation Cytokine-induced beta cell death preferentially affects newly forming beta cells, which implies that replicating beta cells might be more vulnerable to cytokine destruction. Efforts to expand beta cell mass in type 1 diabetes by fostering beta cell replication are likely to fail unless cytokine-induced apoptosis is concurrently suppressed.