EXPOSURE OF RAT PANCREATIC-ISLETS TO RS-61443 INHIBITS BETA-CELL FUNCTION

In this study, the long-term effects of the immunosuppressive drug RS-61443 on pancreatic beta-cell function have been evaluated. For this purpose, isolated rat pancreatic islets were precultured for 6 to 7 days in RPMI 1640 medium + 10% FCS and then cultured for another 6 days in the absence or presence of RS-61443 (15, 60, 120, and 240 mg/L). The islet DNA content was decreased by 20-30% after culture at all concentrations of the drug. At the highest drug concentration, there were disarrangements in the islet architecture. This was probably not confined to only beta-cells, since the ratio of insulin to DNA was not decreased. On day 6, glucose-stimulated insulin secretion was inhibited by 75-90%, whereas rates of islet (pro)insulin biosynthesis and glucose oxidation were not or only slightly affected. After 48 hr of culture in the absence of the drug, the decrease in islet DNA content remained, but the impaired insulin secretion was partly restored. In acute in vitro experiments, RS-61443 initially enhanced glucose-stimulated insulin secretion, but during a second hour of incubation, there was an inhibition. In variance to this latter finding, islet glucose oxidation was inhibited already during the first hour. The present results suggest that longterm exposure to RS-61443 in vitro impairs beta-cell function and this might be due to an inhibition of formation of guanosine metabolites. In other experiments, rats and mice were treated for 6 days with intraperitoneal injections of RS-61443 (70 mg/kg body wt). The pancreatic insulin concentration was not changed, but during glucose tolerance tests, minor impairments were observed. In conclusion, the present data suggest that RS-61443 is potentially harmful to beta-cells.