Repetitive exposure of pancreatic islets to interleukin-1 beta. An in vitro model of pre-diabetes?

The slowly progressing loss of glucose tolerance over years before clinical onset of Type 1 (insulin-dependent) diabetes mellitus may be due to repetitive immunological attacks on the pancreatic beta-cell mass. Accordingly, we studied the effects of repetitive exposure of isolated rat pancreatic islets to the beta-cytotoxic immune-mediator interleukin-1 beta. Islets were exposed thrice to 60 U/ml of recombinant interleukin-1 beta for 24 hr. The islets were allowed to recover for 6 d between the interleukin-1 beta exposure periods. After each of the three interleukin-1 beta exposure periods, islet capacity to release insulin was decreased to 12, 6 and 3% of control, respectively, and islet insulin content decreased to 75, 56 and 21%, respectively. After the two recovery culture periods, the capacity for insulin release reversed to 75 and 30% of control, respectively. An increase in islet insulin content was only seen after the first recovery culture. During repetitive as well as long-term (6 d) interleukin-1 beta exposure of islets, medium accumulation of glucagon was either increased or unaffected. In analogy, beta-cells exposed to interleukin-1 beta for 6 d showed ultrastructural signs of degeneration and cytolysis, whereas alpha-cells were intact. In conclusion, interleukin-1 beta injury to beta-cells was partially reversible, but successive episodes of islet interleukin-1 beta exposure were increasingly detrimental; alpha-cell function and structure did not show susceptibility to damage by interleukin-1 beta. These findings may contribute to our understanding of islet cell behaviour before and during onset of Type 1 diabetes.