TableEdit

Nielsen, K, Karlsen, AE, Deckert, M, Madsen, OD, Serup, P, Mandrup-Poulsen, T and Nerup, J (1999) Beta-cell maturation leads to in vitro sensitivity to cytotoxins. Diabetes 48:2324-32

Pancreatic beta-cells are more sensitive to several toxins (e.g., streptozotocin, 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 investigate if this sensitivity represents an acquired trait during beta-cell maturation, we used two in vitro cultured cell systems: 1) a pluripotent glucagon-positive pre-beta-cell phenotype (NHI-glu) that, after in vivo passage, matures into an insulin-producing beta-cell phenotype (NHI-ins) and 2) a glucagonoma cell-type (AN-glu) that, after stable transfection with pancreatic duodenal homeobox factor-1 (PDX-1), acquires the ability to produce insulin (AN-ins). After exposure to interleukin (IL)-1beta, both of the insulin-producing phenotypes were significantly more susceptible to toxic effects than their glucagon-producing counterparts. Nitric oxide (NO) production was induced in both NHI phenotypes, and inhibition with 0.5 mmol/l N(G)-monomethyl-L-arginine (NMMA) fully protected the cells. In addition, maturation into the NHI-ins phenotype was associated with an acquired dose-dependent sensitivity to the toxic effect of streptozotocin. Our results support the hypothesis that the exquisite sensitivity of beta-cells to IL-1beta and streptozotocin is an acquired trait during beta-cell maturation. These two cell systems will be useful tools for identification of molecular mechanisms involved in beta-cell maturation and sensitivity to toxins in relation to type 1 diabetes.

PubMed

Animals; Catalase/genetics; Cell Differentiation; Cell Survival/drug effects; Cell Survival/physiology; Clone Cells; Cytotoxins/toxicity; Gene Expression Regulation; Glucagonoma; Glucose Transporter Type 1; Glutathione Peroxidase/genetics; HSP70 Heat-Shock Proteins/genetics; Homeodomain Proteins/physiology; Interleukin-1/pharmacology; Islets of Langerhans/cytology; Islets of Langerhans/drug effects; Monosaccharide Transport Proteins/genetics; Pancreatic Neoplasms; Phenotype; Rats; Rats, Inbred Strains; Recombinant Proteins/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells/cytology; Stem Cells/drug effects; Streptozocin/toxicity; Superoxide Dismutase/genetics; Trans-Activators/genetics; Trans-Activators/physiology; Transcription, Genetic; Transfection; Tumor Cells, Cultured