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.

Daidzein and genistein are abundant in soy-rich foods, whose supplementation has been proposed to have beneficial effects on several diseases, including diabetes mellitus and obesity. 17β-estradiol (E2) enhances the expression of the Slc2a4 gene and GLUT4 protein in adipose tissue, increasing glucose consumption and contributing to glycemic control. We investigated, in 3T3-L1 adipocytes, the effect of low and high doses of daidzein and genistein on Slc2a4/GLUT4 expression and the participation of estrogen receptors 1/2 (ESR1/ESR2) in the regulations observed. Differentiated adipocytes were cultivated, for 24 h, in the presence of 17β-estradiol (E2, 10 nM), daidzein (10 nM–150 μM) and genistein (10 nM–50 μM), with or without ESR1 or ESR2 antagonists. Daidzein/genistein at a low dose (10 nM) increased Slc2a4/GLUT4 expression (50%, p < 0.05), an effect abrogated by an ESR1 antagonist, mimicking the effect of E2. However, maximal doses of daidzein and genistein reduced, in a ESR1-mediated mechanism, the expression of mRNA (by 47% and 60%, p < 0.001) and the protein (by 29% and 36%, p < 0.01), respectively, for daidzein and genistein, as compared to E2. In conclusion, in adipocytes, daidzein and genistein have a biphasic ESR1-mediated effect: while low concentrations increase the expression of Slc2a4/GLUT4, high concentrations decrease it, the former predisposing to an adipogenic effect, the latter to a diabetogenic condition.