Epiandrosterone and dehydroepiandrosterone affect glucose oxidation and interleukin-1β effects in pancreatic islets

Isolated rat islets or RINm5F insulinoma cells treated with interleukin- 1β (IL-1β) for 18 h show reduced glucose-sensitive insulin release and increased nitrite formation as a result of nitric oxide synthase induction. Although a phosphodiesterase inhibitor, isobutylmethylxanthine, potentiated insulin release in response to glucose stimulation, the secretory response was not restored to normal in IL-1β-treated islets. Islets that were cultured for 18 h in the presence of IL-1β and epiandrosterone (EA) or dehydroepiandrosterone (DHEA) and then washed responded with a concentration- dependent reversal of the effects of IL-1β on insulin release in the presence of a glucose or glucose plus isobutylmethylxanthine stimulus. In contrast, when EA and DHEA were not washed from the islets before determination of insulin release, the presence of EA or DHEA inhibited insulin release in both freshly isolated and cultured islets. Nitrite formation in islets and RINm5F cells in response to IL-1β was also significantly reduced during culture with EA or DHEA, although nitrite levels were still elevated above control values. Neither steroid affected cell growth or DNA or protein content. Pyrrolidine dithiocarbamate also reduced IL-1β-induced nitrite formation, EA and DHEA inhibited [U-¹⁴C]glucose oxidation in islets and RINm5F cells. Comparison of [1-¹⁴C]glucose and [6- ¹⁴C]glucose oxidation in islets and RINm5F cells when EA was present during culture and metabolic determination indicated that EA inhibited glycolysis and the pentose shunt contribution to glucose utilization. Neither IL-1β in islets nor DHEA in RINm5F cells inhibited pentose shunt activity, although total glucose oxidation and utilization were inhibited. The effects of DHEA and EA on glucose oxidation were rapidly reversible. EA and DHEA reduced glucose-6-phosphate dehydrogenase activity only when added directly to tissue homogenates. Thus, EA and DHEA antagonize the effects of IL-1β on β-cells. Inhibition of glucose metabolism and pentose shunt activity may protect the cells from nitric oxide synthase activation and related toxicities.