And Glycemic Homeostasis: The Basic Role of Nuclear Aldose Reductase Inhibitor supplier estrogen Receptors ESR1/ESR2 in Glucose Transporter GLUT4 RegulationKaren Cristina Rego Gregorio , Caroline Pancera Laurindo and Ubiratan Fabres Machado Department of Physiology and GPR35 Compound Biophysics, Institute of Biomedical Sciences, University of S Paulo, Av. Prof. Lineu Prestes 1524, S Paulo (SP) 05508-900, Brazil; [email protected] (K.C.R.G.); [email protected] (C.P.L.) Correspondence: [email protected]; Tel.: +55-11-3091-7494 These authors contributed equally to this work.Citation: Gregorio, K.C.R.; Laurindo, C.P.; Machado, U.F. Estrogen and Glycemic Homeostasis: The Basic Role of Nuclear Estrogen Receptors ESR1/ESR2 in Glucose Transporter GLUT4 Regulation. Cells 2021, 10, 99. https://doi.org/10.3390/ cells10010099 Received: eight December 2020 Accepted: 4 January 2021 Published: 7 January 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Abstract: Impaired circulating estrogen levels have been associated with impaired glycemic homeostasis and diabetes mellitus (DM), both in females and males. Even so, for the final twenty years, the partnership amongst estrogen, glycemic homeostasis as well as the mechanisms involved has remained unclear. The characterization of estrogen receptors 1 and 2 (ESR1 and ESR2) and of insulin-sensitive glucose transporter sort 4 (GLUT4) finally offered a terrific chance to shed some light on estrogen regulation of glycemic homeostasis. Within this manuscript, we assessment the connection in between estrogen and DM, focusing on glycemic homeostasis, estrogen, ESR1/ESR2 and GLUT4. We review glycemic homeostasis and GLUT4 expression (muscle and adipose tissues) in Esr1-/- and Esr2-/- transgenic mice. We especially address estradiol-induced and ESR1/ESR2-mediated regulation in the solute carrier loved ones two member 4 (Slc2a4) gene, examining ESR1/ESR2-mediated genomic mechanisms that regulate Slc2a4 transcription, specifically these occurring in cooperation with other transcription factors. Furthermore, we address the estradiol-induced translocation of ESR1 and GLUT4 for the plasma membrane. Studies make it clear that ESR1-mediated effects are advantageous, whereas ESR2mediated effects are detrimental to glycemic homeostasis. Hence, imbalance of the ESR1/ESR2 ratio may have critical consequences in metabolism, highlighting that ESR2 hyperactivity assumes a diabetogenic role. Search phrases: estradiol; phytoestrogens; ESR1; ESR2; GLUT4; glycemic homeostasis; diabetes mellitus1. Introduction Within the early occasions of endocrinology, the hypophysis-related modulation of glycemic homeostasis began to be investigated by the 1947 Nobel Prize recipient in Physiology or Medicine, Bernard Houssay. At that time, many hormones associated with hypophyseal axes had extended been described as capable of modulating blood glucose, like estrogens. Indeed, estrogen participation in diabetes mellitus (DM) had currently been investigated in humans and in experimental models [1]. Nevertheless, despite reports that alterations in plasma estrogen concentration could correlate with alterations in blood glucose levels, a direct connection between these variables was not straightforward to become established, since the alterations in estrogen concentration could imply changes in many other hormonal systems, which ultimately might modulate the blood glucose control. Relating to that, the knowledge from the estrogen mechanism of action and.
