INTERLEUKIN-1-BETA (IL-1) DOES NOT REDUCE THE DIABETES INCIDENCE IN DIABETES-PRONE BB RATS

The cytokine interleukin 1 beta (IL-1) has been implicated as a pathog enetic factor in the initial events leading to insulin-dependent diabe tes mellitus. Previous studies investigating the impact of IL-1 on dia betes incidence in spontaneously diabetic rodent models have been conf licting. IL-1 induces anorexia and previous studies are hampered by th e lack of pair-fed controls to the IL-1 treated animals. We report tha t daily injections of 4.0 mu g/kg/day of recombinant human IL-1 (rhIL- 1) for 13 weeks from 25-30 days of age did not alter the incidence of diabetes in the diabetes-prone (DP) BB rats (75%) when compared to pai r-fed, vehicle treated controls (55%, p = 0.18), or to unhandled DP BB rats (80%, p = 0.71). However, IL-1 induced significantly higher bloo d glucose concentrations in the prediabetic period (p < 0.00005) and a t diabetes onset (p < 0.00005) in the DP BB rats and caused episodes o f blood glucose concentrations > 11 mmol/l in the prediabetic period i n 11/20 DP BB rats compared to 4/27 diabetes-resistant (DR) BB rats an d 4/28 Wistar Furth (WF) rats (both p < 0.004), compared to DP BB). Fu rther, rhIL-1 induced fever in 11 weeks in the DP BB rats compared to 3 weeks in the DR BB and 6 weeks in the WF rats. Using high performanc e size exclusion chromatography specific anti-rhIL-1-antibodies were d emonstrated in DR BB and WF, but not in DP BB rats. These antibodies n eutralized the inhibitory effect of rhIL-1 on insulin secretion from i solated islets of Langerhans in vitro. The reduced pyrogenic and endoc rine effect of rhIL-1 in the DR BB and WF rats compared to the DP BB r ats could be explained by the impaired ability of the DP BB rats to pr oduce anti-rhIL-1-antibodies. In conclusion, administration of rhIL-1 modulated the prediabetic period, and produced higher blood glucose co ncentrations at diagnosis, but did not change the diabetes incidence i n DP BB rats. The results are not in conflict with the hypothesis that IL-1 is a pathogenetic factor in IDDM, caused by high local concentra tions of rat IL-1 in the islets during early insulitis. The results al so show the necessity of pair-feeding of the control group to the rhIL -1 group when interpreting data from experiments investigating rhIL-1 effects on diabetes development in animal models.