Comparative analysis of dose-response variability and severity in STZ-induced diabetes: female vs. male NSG mice

Abstract This study evaluated the dose–response relationship of streptozotocin in female NSG mice to identify a dose that reliably induces diabetes mellitus while minimizing animal burden. Although streptozotocin is widely used to model insulin-dependent diabetes in rodents, sex-specific responses are underexplored, and female mice are often excluded due to their reduced sensitivity. We tested single doses ranging from 125 to 225 mg/kg body weight. Concentrations of 125 and 150 mg/kg yielded insufficient diabetes induction, whereas 200 and 225 mg/kg caused rapid, severe hyperglycemia and dramatic weight loss requiring early termination. A dose of 175 mg/kg body weight streptozotocin emerged as optimal, inducing stable hyperglycemia in approximately 90% of the animals with acceptable weight loss and minimal mortality. Compared to males, females required ~ 25 mg more streptozotocin for comparable outcomes, reflecting lower vulnerability likely linked to estrogen signaling. We did not observe significant differences in terms of animal suffering when comparing female to male mice. Additionally, sex-specific diagnostic thresholds for hyperglycemia were identified. These results provide the first dose-response data for female NSG mice, offering refined guidance for preclinical diabetes research and supporting the inclusion of both sexes in experimental design.