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 17b-estradiol (E 2 ). 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 E 2 on glucose homeostasis in male and ovariectomized (OVX) female control and liverspecific Foxo1 knockout (L-F1KO) mice and sought to understand the mechanism by which E 2 regulates gluconeogenesis via an interaction with hepatic Foxo1. In both male and OVX female control mice, subcutaneous E 2 implant improved insulin sensitivity and suppressed gluconeogenesis; however, these effects of E 2 were abolished in L-F1KO mice of both sexes. In our use of mouse primary hepatocytes, E 2 suppressed HGP and gluconeogenesis in hepatocytes from control mice but failed in hepatocytes from L-F1KO mice, suggesting that Foxo1 is required for E 2 action on the suppression of gluconeogenesis. We further demonstrated that E 2 suppresses hepatic gluconeogenesis through activation of estrogen receptor (ER)a-phosphoinositide 3-kinase-Akt-Foxo1 signaling, which can be independent of insulin receptor substrates 1 and 2 (Irs1 and Irs2), revealing an important mechanism for E 2 in the regulation of glucose homeostasis. These results may help explain why premenopausal women have lower incidence of T2D than age-matched men and suggest that targeting ERa can be a potential approach to modulate glucose metabolism and prevent diabetes.

In this paper, a method is presented to analyze the mechanical stress distribution in a pacing lead based on a sequence of paired 2D angiographic images. The 3D positions and geometrical shapes of an implanted pacemaker lead throughout the cardiac cycle were generated using a previously validated 3D modeling technique. Based on the Frenet-Serret formulas, the kinematic property of the lead was derived and characterized. The distribution of curvature and twist angle per unit length in the pacing lead was calculated from a finite difference method, which enabled a rapid and effective computation of the mechanical stress in the pacing lead. The analytical solution of the helix deformation geometry was used to evaluate the accuracy of the proposed numerical method, and an excellent agreement in curvature, twist angle, and stresses was achieved. As demonstrated in the example, the proposed technique can be used to analyze the complex movement and deformation of the implanted pacing lead in vivo. The information can facilitate the future development of pacing leads.