Age-dependent sensitivity to streptozotocin of pancreatic islets isolated from female NOD mice.

Streptozotocin (STZ), a selective beta-cell cytotoxin, given in multiple low doses to susceptible mouse strains causes insulin-dependent diabetes mellitus (IDDM) with an autoimmune pathology. Studies in the human suggest that environmental factors such as viruses and certain toxins may modulate the expression of the disease in genetically-prone individuals and the effect may also be age-dependent. Here we have examined the effects of graded, low doses of STZ on beta-cell function and insulin and DNA contents in vitro in cultured islets isolated from female IDDM-prone NOD mice at 4 weeks and at 8 weeks. Results were compared with islets from age and sex-matched non-diabetes prone C57BL/Ks mice. No changes in islet DNA or insulin contents were observed after an acute 30 min exposure to STZ (0, 1.1, 2.2 and 4.4 mM) in the two strains at each of the age groups. However, the DNA content in the NOD mouse islets tended to be lower at 8 weeks, being significant at 1.1 mM STZ. At 4 weeks, islets from NOD mice had a higher insulin content than the control mice but this declined at 8 weeks when it became comparable to the control strain. STZ caused a dose-dependent inhibition of islet glucose oxidation rates in all groups. However, at 4 weeks, exposure to 2.2 mM STZ resulted in a significantly greater inhibition in NOD mice than in age-matched control mice. This was reversed at 8 weeks when the islets from NOD mice showed a greater resistance to oxidative impairment than from C57BL/Ks mice. In the presence of 16.7 mM glucose, an inhibitory pattern, similar to the glucose oxidation rate, was also observed for insulin release. In the control mice the relative inhibition of insulin release and glucose oxidation rate was similar at 4 and 8 weeks. These results suggest that islets from the NOD mouse at 4 weeks and prior to insulitis are more sensitive to STZ-induced functional impairment. This enhanced sensitivity suggests that cumulative exposure of diabetes-prone islets to low doses of selective beta cell toxins may be a determinant for later development of IDDM.