Previous studies have demonstrated a stimulatory effect of interleukin-1β(IL-1β) on insulin and glucagon release from the perfused rat pancreas, accompanied by selective lysis of 20% ofβ-cells as assessed by electronmicroscopy. However, we have not observed an inhibitory action of IL-1βon insulin release from the perfused pancreas as shown for isolated islets. To test whether periodical exposure of the endocrine pancreas to circulating IL-1βin vivoaffects insulin release from the intact perfused pancreas, rats were treated with daily intraperitoneal injections of 4μg IL-1β/kg or saline for 5 days. On day 5 the pancreata were isolated 2 h after the last injection and perfused from 0 to 72 min with 11 mmol/l D-glucose and from 72 to 84 min with 20 mmol/l D-glucose. Saline or IL-1βwas added from 12 to 72 min.In pancreata from animals pre-treated with IL-1βglucose-stimulated as well as IL-1βpotentiated glucose-stimulated insulin release was almost completely abolished. Furthermore, a decline in insulin release was observed at 1 1 mmol/l D-glucose, in contrast to an increase in insulin release in controls. The total extractable insulin content in pancreata from IL-1βpre-treated rats was higher than in pancreata from saline-treated controls. In contrast to the inhibitory effect ofin vivoadministration of IL-1βon 1β-cell function glucagon secretion was stimulated.These observations suggest that circulating IL-1βis an important modulator ofαa- andβ-cell secretory functionin vivoand that IL-1βshould be considered a contributory pathogenetic factor in the development of insulin-dependent (type I) diabetes mellitus.