Background: Type 2 diabetes (T2D) is a polygenic metabolic disease, characterized by high fasting blood glucose (FBG). The ability of cranberry (CRN) fruit to regulate glycemia in T2D patients is well known. Here, a cohort of 13 lines of the genetically diverse Collaborative Cross (CC) mouse model was assessed for the effect of non- dialyzable material (NDM) of cranberry extract in lowering fasting blood glucose. Methods: Eight-week-old mice were maintained on either a standard chow diet (control group) or a high-fat diet (HFD) for 12 weeks, followed by injections of intraperitoneal (IP) NDM (50 mg/kg) per mouse, three times a week for the next 6 weeks. Absolute FBG (mg/dl) was measured bi-weekly and percentage changes in FBG (%FBG) between weeks 0 and 12 were calculated. Results: Statistical analysis showed a significant decrease in FBG between weeks 0 and 12 in male and female mice maintained on CHD. However, a non-significant in-crease in FBG values was observed in male and female mice maintained on HFD during the same period. Following administration of NDM during the following 6 weeks, the results show a variation in significant levels of FBG lowering between lines, male and female mice and under the different diets. Conclusion: The results suggest that the efficacy of NDM treatment in lowering FGB depends on host genetic background (pharmacogenetics), sex of the mouse (pharmacosex), and diet (pharmacodiet). All these results support the need for follow-up research to better understand and implement a personalized medicine approach/utilization of NDM for reducing FBG.