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.
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Abstract|
December 01 1999
Beta-cell maturation leads to in vitro sensitivity to cytotoxins.
K Nielsen;
K Nielsen
Steno Diabetes Center, Gentofte, Denmark.
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A E Karlsen;
A E Karlsen
Steno Diabetes Center, Gentofte, Denmark.
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M Deckert;
M Deckert
Steno Diabetes Center, Gentofte, Denmark.
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O D Madsen;
O D Madsen
Steno Diabetes Center, Gentofte, Denmark.
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P Serup;
P Serup
Steno Diabetes Center, Gentofte, Denmark.
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T Mandrup-Poulsen;
T Mandrup-Poulsen
Steno Diabetes Center, Gentofte, Denmark.
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J Nerup
J Nerup
Steno Diabetes Center, Gentofte, Denmark.
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Citation
K Nielsen, A E Karlsen, M Deckert, O D Madsen, P Serup, T Mandrup-Poulsen, J Nerup; Beta-cell maturation leads to in vitro sensitivity to cytotoxins.. Diabetes 1 December 1999; 48 (12): 2324–2332. https://doi.org/10.2337/diabetes.48.12.2324
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