Translation of preclinical findings on the efficacy of dietary interventions for metabolic disease to human clinical studies is challenging due to the predominant use of male rodents in animal research. Our objective was to evaluate a combined high-fat (HF) diet and low-dose streptozotocin (STZ) model for induction of type-2 diabetes (T2D) in male and female C57BL/6J mice. We hypothesized that T2D biomarkers would differ significantly between sexes. Mice were administered either a low-fat (LF) diet (10% kcal from fat), or HF diet (60% kcal from fat) + STZ injections (30 mg/kg/d for 3 days). Both sexes gained weight and developed impaired postprandial oral glucose tolerance on the HF+STZ treatment compared to LF. Only male mice on HF + STZ developed fasting hyperglycemia, fasting hyperinsulinemia and insulin resistance, suggesting that the underlying causes of postprandial hyperglycemia differed between sexes. Principal component analysis of measures such as body weights, glucose and insulin concentrations indicated metabolic derangement for males only on HF+STZ treatment, while LF group males and both groups of females significantly overlapped. Based on our data, we accept our hypothesis that the combined high-fat diet and low-dose STZ model for T2D phenotypes differs significantly in its effect on mice based on sex. The HF diet + low-dose STZ model is not useful for studying insulin resistance in females. Other models are needed to model T2D, and study the effects of dietary interventions in this disease, in females. Sexual dimorphism remains a significant challenge for both preclinical and clinical research.