Abstract
Impaired circulating estrogen levels have been related to impaired glycemic homeostasis and diabetes mellitus (DM), both in females and males. However, for the last twenty years, the relationship between estrogen, glycemic homeostasis and the mechanisms involved has remained unclear. The characterization of estrogen receptors 1 and 2 (ESR1 and ESR2) and of insulin-sensitive glucose transporter type 4 (GLUT4) finally offered a great opportunity to shed some light on estrogen regulation of glycemic homeostasis. In this manuscript, we review the relationship 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 specifically address estradiol-induced and ESR1/ESR2-mediated regulation of the solute carrier family 2 member 4 (Slc2a4) gene, examining ESR1/ESR2-mediated genomic mechanisms that regulate Slc2a4 transcription, especially those occurring in cooperation with other transcription factors. In addition, we address the estradiol-induced translocation of ESR1 and GLUT4 to the plasma membrane. Studies make it clear that ESR1-mediated effects are beneficial, whereas ESR2-mediated effects are detrimental to glycemic homeostasis. Thus, imbalance of the ESR1/ESR2 ratio may have important consequences in metabolism, highlighting that ESR2 hyperactivity assumes a diabetogenic role.
Highlights
In the early times of endocrinology, the hypophysis-related modulation of glycemic homeostasis started to be investigated by the 1947 Nobel Prize recipient in Physiology or Medicine, Bernard Houssay
Esr1−/− and Esr2−/− mice, as well as Cyp19a1−/− mice treated with selective Estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2) agonists, revealed that ESR1 activity improves glycemic homeostasis, whereas ESR2 activity impairs glycemic homeostasis, and that is accompanied by an increase and a decrease of muscle glucose transporter member 4 (GLUT4) content, respectively
Considering that the insulin-sensitive glucose transporter GLUT4 (Slc2a4 gene) is fundamental to insulinregulated plasma glucose clearance, the regulations of muscle GLUT4 expression explain the regulations of glycemic homeostasis in Esr1−/− and Esr2−/− mice
Summary
In the early times of endocrinology, the hypophysis-related modulation of glycemic homeostasis started to be investigated by the 1947 Nobel Prize recipient in Physiology or Medicine, Bernard Houssay. We have investigated the estrogen-induced ESR-mediated regulation of SLC2A4/GLUT4 expression, expecting to demonstrate a direct effect of estrogen upon glycemic homeostasis, which could be helpful to ameliorate the diabetes condition. The estrogen-induced improvement of glycemic control was reported in women who developed diabetes related to menopause or ovariectomy [13]. Further investigations revealed a high incidence of both DM in women with gonadal dysgenesis [14] and glucose intolerance in children with Turner syndrome [15] All in all, these data suggest that estrogen would be capable of exerting a beneficial effect on glycemic control, regardless of pancreatic insulin secretion; the estrogeninduced modulation of other hormonal systems (especially those related to the hypophysis) has been considered until recently, compromising the statement that estrogen plays a direct effect on glycemic regulation. These data suggest that, in women, estrogen intake can have opposite effects according to the previous circulating estrogenic (low or high) levels, highlighting the complexity of these effects
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