Streptozotocin (STZ)-Induced Diabetic Mice Model: A Review of Methodology, Importance, and Future Implications

Abstract

The streptozotocin (STZ)-induced diabetic mouse model remains one of the most widely used experimental platforms for investigating type 1 and type 2 diabetes mellitus and their complications. This review synthesizes key advancements in the model, with emphasis on methodological standardization, scientific contributions, and emerging research directions. STZ, a glucosamine-nitrosourea compound, selectively destroys pancreatic β-cells through GLUT2-mediated uptake, DNA alkylation, PARP activation, and oxidative stress, rapidly inducing hypoinsulinemia, sustained hyperglycemia (>250 mg/dL), polyuria, polydipsia, and weight loss. Unlike spontaneous autoimmune models such as NOD mice, the STZ model offers precise temporal control and compatibility with genetically modified strains. In recent times, protocols have shifted from single high-dose (150–200 mg/kg) to multiple low-dose regimens (40–55 mg/kg intraperitoneally daily for 5 days) in young male C57BL/6J mice, incorporating mild insulitis-like inflammation for improved construct validity. Critical refinements include 90-minute anomer equilibration of STZ in neutral buffers, elimination of fasting and sucrose supplementation, and dose-response tailoring, which collectively achieve > 94% success rates, reduce mortality from ~36% to ~7%, and enhance induction of early diabetic nephropathy (tubular injury and kidney hypertrophy). The model’s versatility supports hybrid type 2 diabetes paradigms when combined with high-fat diet or nicotinamide and has enabled detailed mechanistic studies of retinopathy, cardiomyopathy, neuropathy, and cognitive deficits. Despite limitations such as incomplete autoimmune fidelity and potential off-target toxicity, the STZ mouse model continues to accelerate preclinical drug screening and therapeutic development. Future directions prioritize sex-balanced designs, longitudinal multi-omics integration, CRISPR-edited strains, advanced imaging, and international protocol harmonization under ARRIVE guidelines. These innovations will further enhance translational relevance and ethical rigor, positioning the model as a precision platform for 21st-century diabetes research.