Article

Obesity Reduces the Expression of GLUT4 in the Endometrium of Normoinsulinemic Women Affected by the Polycystic Ovary Syndrome

Dipartimento di Scienze Mediche e Chirurgiche dell'Università di Padova-Clinica Medica 3, Via Giustiniani 2, 35128 Padova, Italy.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 01/2005; 1034(1):364-74. DOI: 10.1196/annals.1335.038
Source: PubMed

ABSTRACT

GLUT4 is the most important glucose transporter in insulin-dependent tissues. A decrease of its expression by the adipocytes was reported in polycystic ovary syndrome (PCOS), regardless of obesity and glucose tolerance. In PCOS, abnormal menstrual cycles, abnormal insulin secretory patterns, and obesity, which are risk factors for endometrial diseases, frequently coexist. The endometrial effects of insulin are direct through specific insulin receptors. However, it is unknown whether the endometrium expresses GLUT4 and can be considered an insulin-regulated tissue. In this study, we investigated this question, and we investigated whether obesity modulates this expression in PCOS normoinsulinemic patients. We assayed GLUT4 in the endometrial samples from 18 normoinsulinemic PCOS patients and 9 controls in the advanced follicular phase of the cycle; 10 patients were lean and 8 obese, and all were aged between 23 and 32 years. Most tissue was immediately frozen for RT-PCR; some tissue was saved for histology and immunohistochemistry. GLUT4 mRNA expression was measured in three samples for every patient and expressed as mean +/- SE of an arbitrary unit. In obese PCOS subjects, endometrial GLUT4 expression was significantly lower than in the lean ones (24.0 +/- 6.8 vs. 65.2 +/- 24.4; P < 0.005) and the controls (53.2 +/- 10.7). Lean PCOS and control subjects showed similar values. GLUT4 immunostaining was strong in the epithelial and absent in the stromal cells. We demonstrated endometrial GLUT4 expression. The similar results in lean PCOS and control subjects suggest that endometrial GLUT4 expression is not affected by PCOS itself, whereas it is reduced by obesity in PCOS patients.

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    • "It has been assumed that PCOS-related implantation failure, recurrent miscarriage, and spontaneous abortion [2] [41] are due at least in part to aberrant glucose metabolism in the endometrium [2]. Because hyperandrogenemia is negatively associated with glucose metabolism in women [21], numerous laboratories have taken great interest in the aberrant in vivo expression of GLUT4, a glucose transporter protein, in the endometria of women with PCOS [6] [10] [14] [42] [43] [44]. We also found that the protein levels of GLUT4 were significantly reduced in PCOS patients compared to menstrual-stage-matched normal controls. "
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    ABSTRACT: Conflicting results have been reported regarding whether or not insulin-regulated glucose transporter 4 (GLUT4) is expressed in human and rodent endometria. There is an inverse relationship between androgen levels and insulin-dependent glucose metabolism in women. Hyperandrogenemia, hyperinsulinemia, and insulin resis- tance are believed to contribute to endometrial abnormalities in women with polycystic ovary syndrome (PCOS). However, it has been unclear in previous studies if endometrial GLUT4 expression is regulated by androgen-depen- dent androgen receptors (ARs) and/or the insulin receptor/Akt/mTOR signaling network. In this study, we demon- strate that GLUT4 is expressed in normal endometrial cells (mainly in the epithelial cells) and is down-regulated under conditions of hyperandrogenemia in tissues from PCOS patients and in a 5α-dihydrotestosterone-induced PCOS-like rat model. Western blot analysis revealed reduced endometrial GLUT4 expression and increased AR ex- pression in PCOS patients. However, the reduced GLUT4 level was not always associated with an increase in AR in PCOS patients when comparing non-hyperplasia with hyperplasia. Using a human tissue culture system, we investi- gated the molecular basis by which GLUT4 regulation in endometrial hyperplasia tissues is affected by metformin in PCOS patients. We show that specific endogenous organic cation transporter isoforms are regulated by metformin, and this suggests a direct effect of metformin on endometrial hyperplasia. Moreover, we demonstrate that metfor- min induces GLUT4 expression and inhibits AR expression and blocks insulin receptor/PI3K/Akt/mTOR signaling in the same hyperplasia human tissues. These findings indicate that changes in endometrial GLUT4 expression in PCOS patients involve the androgen-dependent alteration of AR expression and changes in the insulin receptor/ PI3K/Akt/mTOR signaling network.
    Full-text · Article · Mar 2015 · American Journal of Translational Research
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    • "It has been assumed that PCOS-related implantation failure, recurrent miscarriage, and spontaneous abortion [2] [41] are due at least in part to aberrant glucose metabolism in the endometrium [2]. Because hyperandrogenemia is negatively associated with glucose metabolism in women [21], numerous laboratories have taken great interest in the aberrant in vivo expression of GLUT4, a glucose transporter protein, in the endometria of women with PCOS [6] [10] [14] [42] [43] [44]. We also found that the protein levels of GLUT4 were significantly reduced in PCOS patients compared to menstrual-stage-matched normal controls. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Conflicting results have been reported regarding whether or not insulin-regulated glucose transporter 4 (GLUT4) is expressed in human and rodent endometria. There is an inverse relationship between androgen levels and insulin-dependent glucose metabolism in women. Hyperandrogenemia, hyperinsulinemia, and insulin resis- tance are believed to contribute to endometrial abnormalities in women with polycystic ovary syndrome (PCOS). However, it has been unclear in previous studies if endometrial GLUT4 expression is regulated by androgen-depen- dent androgen receptors (ARs) and/or the insulin receptor/Akt/mTOR signaling network. In this study, we demon- strate that GLUT4 is expressed in normal endometrial cells (mainly in the epithelial cells) and is down-regulated under conditions of hyperandrogenemia in tissues from PCOS patients and in a 5α-dihydrotestosterone-induced PCOS-like rat model. Western blot analysis revealed reduced endometrial GLUT4 expression and increased AR ex- pression in PCOS patients. However, the reduced GLUT4 level was not always associated with an increase in AR in PCOS patients when comparing non-hyperplasia with hyperplasia. Using a human tissue culture system, we investi- gated the molecular basis by which GLUT4 regulation in endometrial hyperplasia tissues is affected by metformin in PCOS patients. We show that specific endogenous organic cation transporter isoforms are regulated by metformin, and this suggests a direct effect of metformin on endometrial hyperplasia. Moreover, we demonstrate that metfor- min induces GLUT4 expression and inhibits AR expression and blocks insulin receptor/PI3K/Akt/mTOR signaling in the same hyperplasia human tissues. These findings indicate that changes in endometrial GLUT4 expression in PCOS patients involve the androgen-dependent alteration of AR expression and changes in the insulin receptor/ PI3K/Akt/mTOR signaling network.
    Full-text · Article · Mar 2015 · American Journal of Translational Research
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    • "GLUT4 is a glucose transport protein found in adipose tissues and skeletal muscle [39]. The gene expression level of GLUT4 in skeletal muscle was reduced under the diabetic condition in an animal model [40] as well as in humans [41]. GLUT4 is regulated by AMPK and PPARα, and considerable evidence supports the AMPK-mediated process protects against insulin resistance [42]. "
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    ABSTRACT: Obesity-related disorders, especially metabolic syndrome, contribute to 2.8 million deaths each year worldwide, with significantly increasing morbidity. Eating at regular times and proper food quantity are crucial for maintaining a healthy status. However, many people in developed countries do not follow a regular eating schedule due to a busy lifestyle. Herein, we show that a repeated sense of hunger leads to a high risk of developing visceral obesity and metabolic syndrome in a mouse model (both 3-week and 6-week-old age, 10 mice in each group). The ad libitum (AL) group (normal eating pattern) and the food restriction (FR) group (alternate-day partially food restriction by given only 1/3 of average amount) were compared after 8-week experimental period. The total food consumption in the FR group was lower than in the AL group, however, the FR group showed a metabolic syndrome-like condition with significant fat accumulation in adipose tissues. Consequently, the repeated sense of hunger induced the typical characteristics of metabolic syndrome in an animal model; a distinct visceral obesity, hyperlipidemia, hyperglycemia and hepatic steatosis. Furthermore, we found that specifically leptin, a major metabolic hormone, played a major role in the development of these pathological disorders. Our study indicated the importance of regular eating habits besides controlling calorie intake.
    Full-text · Article · May 2014 · PLoS ONE
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