Rat Pancreatic Islet and RINm5F Cell Responses to Epiandrosterone, Dehydroepiandrosterone and Interleukin-1β

Abstract

Epiandrosterone (EA), dehydroepiandrosterone (DHEA), and their sulfate (-S) and acetate (-A) conjugates were investigated for effects on isolated pancreatic islets and RINm5F insulinoma cells. Interleukin-1β (IL-1β) inhibited glucose-stimulated insulin release in cultured islets, but the presence of EA, EA-A, and to a lesser extent EA-S, preserved the secretory response. IL-1β also increased islet nitrite production, which was antagonized by EA and EA-A, but not by EA-S. EA, EA-A, DHEA, and DHEA-A, but not EA-S and DHEA-S inhibited glucose-stimulated insulin release from islets. This response may be related to the inhibition of glucose transport by EA, EA-A, DHEA, DHEA-A, and DHEA-S, as observed in RINm5F cells. EA, EA-A, DHEA, and DHEA-A also inhibited glucose metabolism in RINm5F cells, whereas EA-S and DHEA-S had no effect. EA, EA-A, DHEA, and DHEA-A, but not the sulfate conjugates, also inhibited RINm5F cell IL-1β-induced nitric oxide synthase (iNOS) activity. IL-1β also increased cytosolic Cu/Zn-superoxide dismutase (SOD) and mitochondrial Mn-SOD in RINm5F cells. EA inhibited RINm5F cell Cu/Zn-SOD in the presence and absence of IL-1β, whereas EA-S increased basal enzyme activity and did not affect the IL-1β response. EA did not affect basal Mn-SOD activity and inhibited IL-1β-stimulated activity, whereas EA-S was without effect. IL-1β had no effect on catalase activity in RINm5F cells, whereas EA, EA-A, and DHEA-A inhibited catalase activity. Thus, EA and DHEA and their acetate congeners protected the β-cell from the inhibitory effects of IL-1β, and inhibited glucose transport and oxidation, and inducible nitricoxide synthase expression. EA and DHEA also had profound effects on Cu/Zn-SOD, which may alter the toxic effects of hydrogen peroxide generation in β-cells.