Interleukin-1 Inhibits Glucose-Modulated Insulin and Glucagon Secretion in Rat Islet Monolayer Cultures*

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Abstract
Recent observations suggest a role for interleukin-1 (IL-1), a polypeptide product of macrophage/monocytic cells, in the immune-mediated destruction of pancreatic islet .beta.-cells observed in type 1 diabetes. In this study, we investigated the effects of IL-1 on both .alpha.- and .beta.-cell secretory functions in rat islet cell monolayer cultures. Insulin release was 97% inhibited after 6 h of incubation in RPMI-1640 medium (11 nM glucose) containing 1 U/ml IL-1 and 96% inhibited after24 h of incubation in medium containing 0.1 U/ml IL-1. The cell content of insulin in the monolayers was decreased by 66% (P < 0.01) after 4 days of incubation in 10 U/ml IL-1; however, after a further 8-day incubation in IL-1-free medium, cell insulin content recovered fully. In contrast, cell glucagon content was decreased by 77% (P < 0.001) after 4 days of incubation in 10 U/ml IL-1 and did not recover after a further 8-day incubation in IL-1-free medium. After an 18-h preincubation in medium with 0.1 and 1 U/ml IL-1, insulin release responses to 16.7 mM glucose were abolished in 4-h incubations, whereas responses to 0.1 mM 3-isobutyl-1-methylxanthine were normal, and after a further 2 and 5 days of incubation in IL-1-free medium, insulin responses to 16.7 mM glucose recovered fully. Similarly, the inhibitory effect of 16.7 mM glucose on glucagon release was lost after an 18-h preincubation in 0.1 and 1 U/ml IL-1, and did not recovery fully after 2 and 5 days in IL-1-free medium, whereas the stimulatory effect of 3-isobutyl-1-methylxanthine on glucagon release was not affected by IL-1. We conclude that (1) IL-1 inhibits glucose-dependent and not cAMP-dependent mechanisms of insulin and glucagon release; (2) inhibition of glucose-stimulated insulin release by IL-1 is reversible, whereas the effect on glucose-modulated glucagon release is not; and (3) IL-1 causes a reversible decrease in the insulin content of islet cells and an irreversible decrease in glucagon content. These actions of IL-1 do not appear to account for the .beta.-cell-specific destruction of islets characteristic of type 1 diabetes.