Studies on the mechanisms causing inhibition of insulin secretion in rat pancreatic islets exposed to human interleukin-1 beta indicate a perturbation in the mitochondrial function.
This study aimed at a more detailed characterization of the mechanisms by which interleukin 1 (IL-1) inhibits insulin secretion. For this purpose, isolated rat pancreatic islets were kept in tissue culture for 5 days in medium RPMI 1640 plus 10% calf serum. The islets were subsequently transferred to the same culture medium containing various test substances plus 1% human serum with or without 25 U/ml human recombinant IL-1 beta. After a culture period of 48 h the islet structure was examined in the electron microscope and the islet function studied in short term incubations in the absence of IL-1. Islets exposed to IL-1 showed ultrastructural signs of degeneration in 10-20% of the B cells while such changes were not found in other types of islet cells. An increased number of secondary lysosomes and occasional myelin figures were observed in the B cells exposed to IL-1. These ultrastructural alterations were, however, reversed in islets cultured in cytokine-free medium for 6 days after the IL-1 treatment. In islets cultured in the presence of 11.1 mM glucose only, or 11.1 mM glucose plus 10 mM nicotinamide, 61 mM dimethyl area, 2 micrograms/ml indomethacin, 10 microM 4-bromophenacyl bromide or 10 microM nordihydroguaiaretic acid, 10 microM phenantroline, and 0.1 or 1.0 microgram/ml cyclosporin A, IL-1 reduced the insulin release by 64-85%. Culture at 5.6 mM glucose did not modify the IL-1-induced inhibition of insulin release, whereas a significant protective effect was observed at 28 or 56 mM glucose. The DNA content in IL-1-exposed islets cultured at 11.1 mM glucose was decreased by about 20% but not in islets cultured at other glucose concentrations. The D-[5-3H]glucose utilization at 16.7 mM glucose was unaffected by IL-1, whereas the oxidation of D-[6-14C]glucose was reduced by 50%. The present results suggest that IL-1-induced inhibition of insulin secretion is related to a disturbed mitochondrial function. This effect is not counteracted by a poly(ADP-ribose) synthetase inhibitor, a hydroxyl radical scavenger, an iron chelator, a T lymphocyte-specific immunosuppressive drug, or inhibitors of phospholipase A2 or inhibitors of prostaglandin and leukotriene synthesis. Thus, IL-1-induced inhibition of insulin secretion seems not to be mediated by the same mechanisms as those causing alloxan- or streptozotocin-induced damage of B cells. Furthermore, the action of IL-1 does not appear to be mediated via arachidonic acid metabolism. Glucose affords some protection, probably by enhancing the B cell mitochondrial function.(ABSTRACT TRUNCATED AT 400 WORDS)
Sandler
S
S
Department of Medical Cell Biology, Uppsala University, Sweden.
Bendtzen
K
K
Borg
L A
LA
Eizirik
D L
DL
Strandell
E
E
Welsh
N
N
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D046508:Culture Techniques; D003524:Cyclosporins / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000648:ultrastructure; D004247:DNA / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D008782:Methylurea Compounds / Q000494:pharmacology; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009536:Niacinamide / Q000494:pharmacology; D010618:Phenanthrolines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins
D000098:Acetophenones; D003524:Cyclosporins; D007328:Insulin; D007375:Interleukin-1; D008782:Methylurea Compounds; D010618:Phenanthrolines; D011994:Recombinant Proteins; D009536:Niacinamide; D009637:Masoprocol; D004247:DNA; C018275:1,1-dimethylurea; D005947:Glucose; C006821:4-bromophenacyl bromide; D007213:Indomethacin