Importance of the concentration of ATP in rat pancreatic β cells in the mechanism of streptozotocin-induced cytotoxicity

Abstract

ABSTRACT The effects of streptozotocin (STZ) and N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) on monolayer cultures of rat pancreatic β cells were compared. The intracellular NAD concentration was markedly decreased by both 2 mmol STZ/l and 13·6 μmol MNNG/l, but insulin secretion was decreased significantly only by STZ. The intracellular ATP level decreased rapidly and in a time-dependent manner with STZ, but decreased less on treatment with MNNG: 80% decrease with STZ but only 35% decrease with MNNG in 12 h in the cells exposed to the chemicals for 1 h and then washed thoroughly. STZ decreased oxygen consumption of rat liver mitochondria in a time- and dose-dependent manner and enhanced the generation of hydroxyl radicals (DMPO-adducts). This enhancement was doubled on the addition of succinate as a substrate. Mitochondrial ATP production was also decreased significantly by STZ, but not by MNNG. Thus the marked depletion of intracellular ATP in β cells by STZ seems to be due mainly to a direct effect on mitochondrial production. From these results, we suggest that the cytotoxic effect of STZ in pancreatic β cells is due to a reduction in the intracellular level of ATP, rather than of NAD. Journal of Endocrinology (1990) 127, 161–165