Studies on the Mechanisms Causing Inhibition of Insulin Secretion in Rat Pancreatic Islets Exposed to Human Interleukin-1β Indicate a Perturbation in the Mitochondrial Function*

Abstract

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-1β. 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 cytokinefree medium for 6 days after the IL-1 treatment. In islets cultured in the presence of 11.1 DIM glucose only, or 11.1 mM glucose plus 10 mM nicotinamide, 61 mM dimethyl area, 2 μg/ml indomethacin, 10 μM 4-bromophenacyl bromide or 10 ΔM nordihydroguaiaretic acid, 10 μM phenantroline, and 0.1 or 1.0 μg/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. It is, however, not clear whether IL-1 primarily affects B cell mitochondria. (Endocrinology124: 1492-1501, 1989)