Testosterone Modulates the Expression of Molecules Linked to Insulin Action and Glucose Uptake in Endometrial Cells

Abstract

Polycystic ovary syndrome (PCOS) is a common hyperandrogenic disorder associated with insulin resistance. Insulin exerts its metabolic function by activating the PI3K/Akt pathway and favoring glucose uptake. Caveolin-1 is a scaffolding protein which increases insulin receptor (IR) stability. Alternatively, activation of IR increases caveolin-1 phosphorylation on tyrosine-14. Furthermore, endometrial tissue from PCOS patients is proposed to be insulin resistant; however, the particular role of testosterone in modulating the metabolic effects of insulin remains unexplored in endometrial stromal cells. To evaluate whether androgens modulate the response to insulin, T-HESCs cells were stimulated with 100 nM testosterone for 24 h and changes in the protein levels of caveolin-1, IR, and Akt were determined by Western blotting (WB). After testosterone treatment, the consequences of acute insulin stimulation were evaluated by WB analysis of phospho-S473Akt and phospho-Y14Caveolin-1, as well as by measuring glucose incorporation analyzing 2-deoxyglucose (2-DOG) uptake. For cells pretreated with testosterone, higher IR, IRS-1, and caveolin-1 protein levels compared with control conditions were detected. However, in testosterone treated cells acute insulin stimulation did not increase phospho-S473Akt and phospho-Y14caveolin-1 levels and reduced 2-DOG uptake was observed compared to control cells. Our results suggest that testosterone may have a detrimental role on the metabolic effects of insulin in endometrial stromal cell cultures. Thus, the high androgen levels in patients with PCOS may favor insulin resistance observed in endometria from these women.

Dehydroepiandrosterone-induced activation of mTORC1 and inhibition of autophagy contribute to skeletal muscle insulin resistance in a mouse model of polycystic ovary syndrome

“…Decreased insulin-stimulated glucose transport in skeletal muscle has been shown to be a major contributing factor to IR in patients with T2D and obesity. Additionally, it has been reported that T reduced insulin-stimulated glucose uptake in cultured female adipocytes [ 21 ] and endometrial cells [ 34 ]. In the present work, we demonstrated that T decreased insulin-stimulated GLUT4 translocation and glucose uptake in C2C12 myotubes, which promoted insulin resistance in these cells.…”

Role of gut microbiota in the development of insulin resistance and the mechanism underlying polycystic ovary syndrome: a review

“…Changes in endometrial function may also be a significant cause of low fertility in PCOS patients. Insulin resistance, as a characteristic metabolic feature in PCOS, affects the physiological function in uterine endometrium relating to endometrial receptivity(ER) [35,36]. The ER of patients with PCOS is worse than that of normal women [37].…”

Emerging role for dysregulated decidualization in the genesis of preeclampsia

“…Several diseases have been reported to both impair decidualization and predispose to preeclampsia including polycystic ovarian syndrome [79–84], obesity [79, 80, 85, 86], diabetes mellitus [87–89], and endometriosis [90–92]. These comorbidities may exert their disruptive action on the endometrium through anomalous inflammation, exaggerated production of androgens, insulin, and homocysteine, as well as pathological epigenetic modifications [79, 91, 93–96]. Indeed, epigenetic dysregulation is another likely instigating factor, insofar as much of the normal biological process of decidualization is epigenetically regulated [97–103].…”