DIFFERENTIAL METABOLITE ACCUMULATION MAY BE THE CAUSE OF STRAIN DIFFERENCES IN SENSITIVITY TO STREPTOZOTOCIN-INDUCED BETA-CELL DEATH IN INBRED MICE

Inbred strains of mice vary in their sensitivity to the diabetogenic e ffects of streptozotocin (STZ). To investigate the basis for this stra in difference we exposed islet cells from two strains of mice that dif fer in sensitivity to the drug. We examined them morphologically and m easured islet NAD + NADH content, streptozotocin metabolite accumulati on, glucose transport capacity, Glut2 levels and medium nitrite accumu lation. C57b1/6J mice were more sensitive to STZ than Balb/c mice as j udged by the extent of pancreatic insulin depletion and beta cell deat h, in vivo and in vitro. The mode of cell death was necrosis. After a 30-min in vitro exposure to the drug the more sensitive C57bl/6J islet s contained higher levels of streptozotocin metabolites and less NAD NADH than the more resistant Balb/c islets. The lack of any strain di fferences in 3-O-methyl glucose transport, Glut2 levels and medium nit rite accumulation suggested that STZ transport and nitric oxide metabo lism were not responsible for differences in STZ sensitivity and metab olite accumulation. Thus the strain differences in STZ sensitivity app ears to be due to intracellular events within the beta cell occurring after STZ transport and before NAD + NADH depletion. STZ metabolite ac cumulation appears to be associated with STZ sensitivity. Further stud ies are warranted to determine if differential STZ metabolite accumula tion is responsible for STZ sensitivity.