caa a22 4500 475771710 CHVBK 20180406123619.0 cr unu---uuuuu 170329e20001101xx s 000 0 eng 10.1007/s001250051564 doi (NATIONALLICENCE)springer-10.1007/s001250051564 Relative importance of transport and alkylation for pancreatic beta-cell toxicity of streptozotocin [Elektronische Daten] [M. Elsner, B. Guldbakke, M. Tiedge, R. Munday, S. Lenzen] Abstract : Aims/hypothesis. The role of selective uptake and alkylation in the diabetogenic action of streptozotocin was investigated in bioengineered RINm5F insulin-producing cells, with different expression levels of the glucose transporter GLUT2, by comparing the toxicity of streptozotocin with that of four chemically related alkylating compounds, N-methyl-N-nitrosourea (MNU), N-ethyl-N nitrosourea (ENU), methyl methanesulphonate (MMS) and ethyl methanesulphonate (EMS). Methods. GLUT2 expressing RINm5F cells were generated through stable transfection of the rat glucose transporter GLUT2 cDNA under the control of the cytomegalovirus promoter in the pcDNA3 vector. Viability of the cells was determined using a microtitre plate-based 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. Results. Cells expressing the glucose transporter GLUT2 were much more susceptible to streptozotocin toxicity than control cells due to the uptake of streptozotocin by this specific glucose transporter. In contrast, the GLUT2 expression had no effect upon the toxicity of MNU, ENU, MMS or EMS. Although the latter substances are, like streptozotocin, cytotoxic through their ability to cause DNA alkylation, they are not diabetogenic because they are not taken up through the glucose transporter GLUT2. Conclusion/interpretation. Our results are consistent with the central importance of selective uptake and alkylating activity in the mechanism of streptozotocin diabetogenicity. Alkylation of DNA leads to necrosis of pancreatic beta cells and thus to a state of insulin-dependent diabetes mellitus, well-known as streptozotocin diabetes in experimental diabetes research. [Diabetologia (2000) 43: 1528-1533] Springer-Verlag Berlin Heidelberg, 2000 Keywords Streptozotocin nationallicence diabetes nationallicence RINm5F cells nationallicence streptozotocin derivatives nationallicence glucose transporter GLUT2 nationallicence Elsner M. Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany, DE aut Guldbakke B. Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany, DE aut Tiedge M. Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany, DE aut Munday R. AgResearch, Ruakura Agricultural Research Centre, Hamilton, New Zealand, NZ aut Lenzen S. Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany, DE aut https://doi.org/10.1007/s001250051564 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s001250051564 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Elsner M. Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany, DE aut NATIONALLICENCE 700 1- Guldbakke B. Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany, DE aut NATIONALLICENCE 700 1- Tiedge M. Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany, DE aut NATIONALLICENCE 700 1- Munday R. AgResearch, Ruakura Agricultural Research Centre, Hamilton, New Zealand, NZ aut NATIONALLICENCE 700 1- Lenzen S. Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany, DE aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer