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.
Helqvist
S
S
Steno Memorial Hospital, Gentofte, Denmark.
Zumsteg
U W
UW
Spinas
G A
GA
Palmer
J P
JP
Mandrup-Poulsen
T
T
Egeberg
J
J
Nerup
J
J
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004247:DNA / Q000032:analysis; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005934:Glucagon / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology
D007328:Insulin; D007375:Interleukin-1; D011994:Recombinant Proteins; D004247:DNA; D005934:Glucagon