Changes in the Expression of Insulin Signaling Pathway Molecules in Endometria from Polycystic Ovary Syndrome Women with or without Hyperinsulinemia

Abstract

Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disorder associated with insulin resistance and compensatory hyperinsulinemia. Scarce information is available on the expression of molecules involved in the insulin pathway in endometria from women with PCOS. Therefore, we examined the protein levels of insulin-signaling molecules, like insulin receptor, insulin-receptor substrate (IRS)-1, pIRS-1Y612, Akt, AS160, pAS160T642 and GLUT4 in endometria from PCOS women with or without hyperinsulinemia. Protein levels were assessed by Western blot and immunohistochemistry in 21 proliferative-phase endometria from control women (CE = 7), normoinssulinemic PCOS women (PCOSE-NI = 7) and hyperinsulinemic PCOS women (PCOSE-HI = 7). The data show no differences in the expression of insulin receptor between all groups as assessed by Western blot; however, IRS-1 and pIRS-1Y612 were lower in PCOSE-HI than controls and PCOSE-NI (P < 0.05). AS160 was detected in all analyzed tissues with similar expression levels between groups. Importantly, PCOSE-HI exhibited lower levels of pAS160T642 (P < 0.05) and of GLUT4 (P < 0.05) compared with CE. The immunohistochemistry for insulin receptor, IRS-1, Akt, AS160 and GLUT4 showed epithelial and stromal localization; IRS-1 staining was lower in PCOSE-HI (P < 0.05). In conclusion, human endometrium has the machinery for glucose uptake mediated by insulin. The diminished expression of GLUT4, as well as the lower level of pIRS-1Y612 and pAS160T642 exhibited by PCOSE-HI, suggests a disruption in the translocation of vesicles with GLUT4 to the cell surface in these patients.

Endometrial signaling pathways during ovarian stimulation for assisted reproduction technology

“…The lower mRNA levels of IGFRI and InsR in the present study was similar to what occurred in opposite conditions of proliferative phase endometria of women with PCOS (29). It has been postulated that, in patients with PCOS, hyperinsulinemia would cause insulin binding to IGFRI, in addition to InsR, and this would be responsible for cell proliferation and its outcomes, endometrial hyperplasia, and carcinoma.…”

Effects of Metformin on the Expression of GLUT4 in Endometrium of Obese Women with Polycystic Ovary Syndrome1

“…However, whether the reduction of GLUT4 expression is related to endometrial cell function remains unclear. Fornes et al [26] recently investigated insulin receptor substrates IRS-1-and AS160-related protein expression in the endometrium and found that IRS-1 and AS160 expression was decreased in patients with PCOS and hyperinsulinemia, which led to a reduction of the expression and translocation capacity of GLUT4, affecting endometrial glucose metabolism.…”

Glucose transporters in the uterus: an analysis of tissue distribution and proposed physiological roles

“…However, several groups have presented evidence that SLC2A4 expression is decreased in endometrial biopsies from women with PCOS versus control (Mozzanega et al . 2004, Fornes et al . 2010, Kohan et al .…”