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Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of type 2 diabetes (T2D) compared with age-matched men, but this advantage disappears after menopause with disrupted glucose homeostasis, in part owing to a reduction in circulating 17β-estradiol (E₂). Fasting hyperglycemia is a hallmark of T2D derived largely from dysregulation of hepatic glucose production (HGP), in which Foxo1 plays a central role in the regulation of gluconeogenesis. Here, we investigated the action of E₂ on glucose homeostasis in male and ovariectomized (OVX) female control and liver-specific Foxo1 knockout (L-F1KO) mice and sought to understand the mechanism by which E₂ regulates gluconeogenesis via an interaction with hepatic Foxo1. In both male and OVX female control mice, subcutaneous E₂ implant improved insulin sensitivity and suppressed gluconeogenesis; however, these effects of E₂ …