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)
Insulin-dependent diabetes mellitus (IDDM) is characterized by a progressive autoimmune destruction of the pancreatic 13-cells. One of the best-suited animal models for IDDM is the nonobese diabetic (NOD) mouse. In this investigation pancreatic islets were isolated from female NOD mice aged 5-7, 8-11, and 12-13 wk and examined immediately (day 0) or after 7 d of culture (day 7). The mice showed a progressive disturbance in glucose tolerance with age, and a correspondingly increased frequency of pancreatic insulitis. Islets isolated from the oldest mice often contained inflammatory cells on day 0, which resulted in an elevated islet DNA content. During culture these islets became depleted of infiltrating cells and the DNA content of the islets decreased on day 7. Islets of the eldest mice failed to respond with insulin secretion to high glucose, whereas a response was observed in the other groups. After culture all groups of islets showed a markedly improved insulin secretion. Islets from the 12-13-wk-old mice displayed a lower glucose oxidation rate at 16.7 mM glucose on day 0 compared with day 7. Islet (pro)insulin and total protein biosynthesis was essentially unaffected. In conclusion, islets obtained from 12-13-wk-old NOD mice exhibit an impaired glucose metabolism, which may explain the suppressed insulin secretion observed immediately after isolation. This inhibition of 3-cell function can be reversed in vitro. Thus, there may be a stage during development of IDDM when 83-cell destruction can be counteracted and 13-cell function restored, provided the immune aggression is arrested. (J.
In order to further characterize the actions of recombinant interleukin-1 beta (rIL-1 beta) on the function of insulin-producing cells, the effects of different concentrations of the cytokine were studied on islets obtained from four different mouse strains (NMRI, NOD, C57BL/6, and C57BL/Ks). For this purpose the islets were exposed to rIL-1 beta (25, 50, or 100 U/ml) for a 48-h period in medium RPMI 1640 containing 10% calf serum and 11.1 mM glucose. In all groups and at the various rIL-1 beta concentrations tested, there was a similar 30-50% inhibition in glucose-induced insulin release, a 70-80% decrease in islet insulin content, and no significant differences in islet DNA content or insulin accumulation in the culture medium. To clarify the mechanisms underlying the decreased islet insulin content, rates of (pro)insulin biosynthesis and insulin messenger RNA (mRNA) contents were determined. Exposure of NMRI and C57BL/6 islets to 50 U/ml rIL-1 beta reduced the (pro)insulin biosynthesis by 40-50% and the insulin mRNA contents by 80-90%. The cytokine also induced an increased cellular content of the heat shock protein hsp70, as measured by western blot analysis, and a decrease in DNA biosynthesis, as measured by [methyl-3H]thymidine incorporation. However, exposure to rIL-1 beta did not decrease islet total protein biosynthesis, glucose oxidation, ATP content, ATP/ADP ratio, cAMP content, or polyamine contents. In conclusion, these data suggest that exposure of mouse islets to rIL-1 beta reduces DNA synthesis, insulin mRNA levels, and the biosynthesis of (pro)insulin, without equally impairing other cellular functions. The mechanisms behind these reductions seem to be different from those observed in rat islets, where a rIL-1 beta-induced impairment of substrate metabolism at the mitochondrial level seems to be related to the decrease of several cellular functions.
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