Endocrine Abstracts

Diabetes mellitus (DM) is an important cause of morbidity and mortality on a global scale. The pathophysiology of DM involves insulin resistance, even in insulin-treated type 1 DM, which in turn is related to the amount of glucose transporter GLUT4 (Slc2a4 gene). Estrogen activity can be mediated by two distinct receptors (ESR1 and ESR2) and may involve genomic and non-genomic mechanisms. Estrogen has been described as involved in glycemic homeostasis, but the related mechanisms are only now beginning to be investigated. Previous studies conducted by our group have demonstrated that estradiol (E2) can modulate the Slc2a4/GLUT4 expression in muscle and adipose cells and have suggested that the ESR1- or ESR-mediated effects may be different. The present study seeks to demonstrate the ESR1- and ESR2-induced effects upon the Slc2a4/GLUT4 expression in adipose cells. Differentiated 3T3-L1 adipocytes were treated with 10 nM E2, 10 nM PPT (ESR1 agonist), 1μ MPP (ESR1 antagonist) and 100 nM DPN (ESR2 agonist) alone, or E2+PPT, E2+MPP and E2+DPN (in the same concentrations), for 24h. Oil Red (OR) staining for analysis of cell differentiation, RT-qPCR for Slc2a4 mRNA quantification and Western blotting for GLUT4 protein quantification were used. Differentiation of 3T3-L1 cells was successfully achieved and similarly preserved after the treatments. E2 and PPT promoted a similar increase (2 to 3 folds, P<0.05) in Slc2a4/GLUT4 expression; and their association did not induce any additional effect. The presence of MPP or DPN in E2-treated cells abrogates the E2 enhancer effect upon the Slc2a4/GLUT4 expression (P<0.05). Curiously, MPP alone was capable of reducing (P<0.01) the Slc2a4/GLUT4 expression as compared to that of control cells (cultivated without E2), suggesting some enhancer effect of ESR1 even in the absence of the ligand. Therefore, E2 increases the Slc2a4/GLUT4 expression in adipocytes by an ESR1-mediated mechanism; an effect that can be counterbalanced by the hyperactivation of ESR2. These data indicate that the E2-induced and ESR1-mediated effects increase the GLUT4 expression, contributing to the improvement of cellular glucose uptake, which can explain a beneficial effect of estrogen upon glycemic homeostasis. On the other hand, the hyperactivity of ESR2, by repressing the GLUT4 expression, may play a diabetogenic effect