Evidence for the Presence of Glucose Transporter 4 in the Endometrium and Its Regulation in Polycystic Ovary Syndrome Patients

Mioni, Roberto; Chiarelli, Silvia; Xamin, Nadia; Zuliani, L.; Granzotto, Marnie; Mozzanega, Bruno; Maffei, Pietro; Martini, Chiara; Blandamura, Stella; Sicolo, Nicola; Vettor, Roberto

doi:10.1210/jc.2003-032028

Cited by 66 publications

(49 citation statements)

References 43 publications

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“…In the present investigation we found that PCOSE-HI exhibited a significant decrease of GLUT4 protein levels compared with control endometria. This observation is in agreement with previous reports by Mozzanega and Mioni (27,28), who showed differences in endometrial GLUT4 level between nonhyperinsulinemic and hyperinsulinemic women with PCOS. Moreover, this difference was more drastic in obese women with hyperinsulinemia compared with lean patients with high insulin levels.…”

Section: Discussionsupporting

confidence: 94%

“…Moreover, this difference was more drastic in obese women with hyperinsulinemia compared with lean patients with high insulin levels. From these data, Mioni et al (27) proposed obesity as a determinant factor for reduced levels of GLUT4 in the cells. In our work, all of the PCOS patients were overweight and most of the PCOS women with hyperinsulinemia were obese; therefore we did not separate lean from obese women.…”

Section: Discussionmentioning

confidence: 99%

“…Mioni et al (27) reported diminished levels of GLUT4 mRNA and protein in endometria from PCOS women who were normoinsulinemic compared with controls and that this decrease was even greater in PCOS women with hyperinsulinemia and obesity (27,28). Nevertheless, scarce information is available related to the expression of other molecules of the insulin signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

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

Fornes

Ormazábal

Rosas

et al. 2009

Mol Med

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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.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Fornes

Ormazábal

Rosas

et al. 2009

Mol Med

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show abstract

“…Because other GLUTs were demonstrated to have expression in endometrium, [27][28][29][30] and because GLUT8 appeared to be hormonally regulated, 27,30,31 we hypothesized that GLUT1 and GLUT8 would be overexpressed in endometrial cancer compared to benign endometrial tissue, controlled for menopausal status. As with the upregulation of glucose transporters in other cancers, the upregulation of GLUT1 and GLUT8 may identify poorly differentiated, thus more aggressive endometrial tumors.…”

Section: Discussionmentioning

confidence: 99%

GLUT1 and GLUT8 in endometrium and endometrial adenocarcinoma

et al. 2006

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Glucose is provided to cells by a family of glucose transport facilitators known as GLUTs. These transporters are expressed in a tissue specific manner and are overexpressed in many primary tumors of these tissues. Regulation of glucose transport facilitator expression has been demonstrated in endometrial tissue and endometrial adenocarcinoma. The following experiments were conducted to quantify and localize the expression of GLUT1 and GLUT8 in benign endometrium and compare this expression to endometrial cancer. Endometrial tissue samples were obtained from random hysterectomy specimens of patients with benign indications for surgery and endometrial cancer. Immunoblot and immunolocatization studies were performed using GLUT1 and GLUT8 specific antisera. Endometrial samples from 65 women who had undergone hysterectomy were examined (n ¼ 38 benign, n ¼ 27 malignant). A 44 and a 35.4 kDa immunoreacive species was demonstrated in endometrium and endometrial cancer for GLUT1 and GLUT8, respectively. Upregulation of GLUT1 expression was demonstrated with increasing grade of tumors (Po0.002). GLUT8 expression was increased in all tumor subtypes compared to atrophic endometrium (Po0.001). Apical localization by GLUT1 and GLUT8 was demonstrated in endometrial glands. GLUT1 and GLUT8 demonstrated diffuse intracellular localization in the cancer subtypes. GLUT1 and GLUT8 are expressed in both human endometrium and endometrial cancer. There appears to be a step-wise progression in GLUT1 and GLUT8 expression as tumor histopathology worsens. GLUT1 and GLUT8 may be important markers in tumor differentiation, as well as providing energy to rapidly dividing tumor cells.

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“…To fulfill its function, the endometria need high supply of energy, particularly from glucose intake and its posterior metabolism. In this aspect, results from our laboratory and other groups indicate that some molecules involved in the insulin signaling pathway could be altered in the endometrium of women with PCOS (PCOSE; Mioni et al 2004. In fact, we have previously shown that phosphorylation of AKT at Ser473 is increased in the PCOSE , Villavicencio et al 2009).…”

Section: Introductionmentioning

confidence: 78%

Role of the transcriptional factors FOXO1 and PPARG on gene expression of SLC2A4 in endometrial tissue from women with polycystic ovary syndrome

Kohan¹,

Carvajal²,

Gabler³

et al. 2010

Reproduction

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Fifty to seventy percent of patients with polycystic ovary syndrome (PCOS) present hyperinsulinemia. On the other hand, reports indicate that forkhead box class O 1 (FOXO1) and peroxisome proliferator-activated receptor-g (PPARG) are involved in the insulin signaling pathway, regulating the gene expression of SLC2A4 (GLUT4). The negative effect of FOXO1 over PPARG transcription disappears when FOXO1 is phosphorylated (p-FOXO1) and excluded from the nucleus, whereas PPARG can suppress gene expression of SLC2A4. Scarce knowledge is available in endometrium of women with PCOS and hyperinsulinemia (PCOSE h-Ins) about the role of these factors. We aimed to evaluate whether the endocrine and metabolic status of PCOS modify the levels of gene and protein expression of FOXO1, PPARG, and SLC2A4 in the endometria from hyperinsulinemic PCOS women compared with controls. In endometria from control (CE, nZ7) or PCOSE h-Ins (nZ7), we determined the subcellular location and protein levels of p-FOXO1Ser319 and FOXO1/FOXO4 by immunohistochemistry and western blot respectively; gene and/or protein levels of PPARG and SLC2A4 were evaluated by RT-PCR and/or western blot. Cytoplasm location for FOXO1 and p-FOXO1Ser319 was immunodetected in both groups of endometria, showing significantly higher staining in PCOSE h-Ins for these proteins (P!0.05). In PCOSE h-Ins, gene and protein levels of PPARG were significantly higher than in CE, whereas SLC2A4 mRNA was decreased (P!0.05). In conclusion, the derepression of PPARG transcription by the high levels of p-FOXO1Ser319 could partially account for the lower levels of SLC2A4 found in PCOSE h-Ins, suggesting an alteration of the endometrial function in these patients.

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Evidence for the Presence of Glucose Transporter 4 in the Endometrium and Its Regulation in Polycystic Ovary Syndrome Patients

Cited by 66 publications

References 43 publications

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

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

GLUT1 and GLUT8 in endometrium and endometrial adenocarcinoma

Role of the transcriptional factors FOXO1 and PPARG on gene expression of SLC2A4 in endometrial tissue from women with polycystic ovary syndrome

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