beta-cell maturation leads to in vitro sensitivity to cytotoxins

Pancreatic beta-cells are more sensitive to several toxins (e.g., streptozo tocin, alloxan, cytokines) than the other three endocrine cell types in the islets of Langerhans. Cytokine-induced free radicals in beta-cells may be involved in beta-cell-specific destruction in type 1 diabetes. To investiga te if this sensitivity represents an acquired trait during beta-cen maturat ion, me used two in vitro cultured cell systems: 1) a pluripotent glucagon- positive pre-beta-cell phenotype (NHI-glu) that, after in vivo passage, mat ures into an insulin-producing beta-cell phenotype (NHI-ins) and 2) a gluca gonoma cell-type (AN-glu) that, after stable transfection with pancreatic d uodenal homeobox factor-1 (PDX-1), acquires the ability to produce insulin (AN-ins). After exposure to interleukin (IL)-1 beta, both of the insulin-pr oducing phenotypes were significantly more susceptible to toxic effects tha n their glucagon-producing counterparts. Nitric oxide (NO) production was i nduced in both NHI phenotypes, and inhibition with 0.5 mmol/l N-G-monomethy l-L-arginine (NMMA) fully protected the cells. In addition, maturation into the NHI-ins phenotype was associated with an acquired dose-dependent sensi tivity to the toxic effect of streptozotocin. Our results support the hypot hesis that the exquisite sensitivity of beta-cells to IL-I beta and strepto zotocin is an acquired trait during beta-cell maturation. These two cell. s ystems will be useful tools for identification of molecular mechanisms invo lved in beta-cen maturation and sensitivity to toxins in relation to type 1 diabetes.