title: Beta-cell maturation leads to in vitro sensitivity to cytotoxins.
abstract: 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.
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Nielsen
authors.forename: A E
authors.initials: AE
authors.lastname: Karlsen
authors.forename: M
authors.initials: M
authors.lastname: Deckert
authors.forename: O D
authors.initials: OD
authors.lastname: Madsen
authors.forename: P
authors.initials: P
authors.lastname: Serup
authors.forename: T
authors.initials: T
authors.lastname: Mandrup-Poulsen
authors.forename: J
authors.initials: J
authors.lastname: Nerup
mesh_terms: D000818:Animals; D002374:Catalase / Q000235:genetics; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002999:Clone Cells; D003603:Cytotoxins / Q000633:toxicity*; D005786:Gene Expression Regulation; D005935:Glucagonoma; D051272:Glucose Transporter Type 1; D005979:Glutathione Peroxidase / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000502:physiology; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D010190:Pancreatic Neoplasms; D010641:Phenotype; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D013311:Streptozocin / Q000633:toxicity*; D013482:Superoxide Dismutase / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D003603:Cytotoxins; D051272:Glucose Transporter Type 1; D018840:HSP70 Heat-Shock Proteins; D018398:Homeodomain Proteins; D007375:Interleukin-1; D009004:Monosaccharide Transport Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D013311:Streptozocin; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase