title: Metformin augments the levels of molecules that regulate the expression of the insulin-dependent glucose transporter GLUT4 in the endometria of hyperinsulinemic PCOS patients.
abstract: OBJECTIVE
  Does treatment with the insulin sensitizer metformin modify the levels and activation of proteins related to the expression of the insulin-dependent glucose transporter (GLUT4), such as adenosine monophosphate-activated protein kinase (AMPK) and myocyte enhancer factor 2A (MEF2A), in endometria from hyperinsulinemic hyperandrogenemic polycystic ovary syndrome (PCOS h-Ins) patients?
  
  
  CONCLUSIONS
  In PCOS h-Ins patients, metformin increases endometrial levels of GLUT4 mRNA and protein levels by normalizing the quantity and activation of molecules that regulate GLUT4 expression to healthy values. These changes could improve endometrial metabolic function.
  
  
  BACKGROUND
  PCOS is an endocrine-metabolic disorders closely associated with insulin resistance. In particular, the insulin signaling pathway is impaired in endometria from these patients and the concentration of GLUT4, as well as the molecules involved in its translocation to the cell surface, is decreased. However, there are limited data about the mechanisms that regulate the GLUT4 expression in the endometria and the effect of metformin on them.
  
  
  METHODS
  This is a case-control study in the setting of a research unit, approved by the Ethical Committees of our institution. The groups whose endometria were studied were PCOS h-Ins (n = 8); PCOS patients with hyperandrogenemia hyperinsulinemia taking only metformin for at least 3 months (PCOS-MTF, n = 8) and healthy fertile women at the time of hysterectomy because of benign pathology as controls (CE, n = 8).
  
  
  METHODS
  Steroids and sex hormone-binding globulin were measured and glucose and insulin levels were evaluated during an oral glucose tolerance test. Protein levels for αAMPK (catalytic subunit of AMPK), phosphorylated (p)-AMPKαThr(172) (activating phosphorylation site), MEF2A, p-MEF2AThr312 (activating phosphorylation site) and GLUT4 were assessed by western blot and immunohistochemistry. In addition, GLUT4 gene expression was evaluated by RT-PCR.
  
  
  RESULTS
  We found significantly lower levels of MEF2A and p-MEF2AThr312 in PCOS h-Ins compared with CE endometria (P < 0.05). Also, we detected lower levels of p-AMPKαThr(172) in PCOS h-Ins endometria compared with the PCOS-MTF group (P < 0.05). The ratios of phospho-AMPK/total AMPK and phospho-MEF2A/total MEF2A were significantly increased in the PCOS-MTF compared with the PCOS h-Ins group (P < 0.05). The RT-PCR experiments showed lower levels of GLUT4 mRNA transcripts in PCOS h-Ins compared with PCOS-MTF-treated group (P < 0.05), the protein levels of GLUT4 were decreased in a similar way.
  
  
  CONCLUSIONS
  The limited number of patients included in this study who presented large clinical variability. Therefore, it would be necessary to recruit a greater number of patients to minimize our data dispersion in order to prove the clinical benefits of metformin described by others.
  
  
  CONCLUSIONS
  Since the insulin sensitizer metformin increases the expression of the GLUT4, it may improve endometrial physiology in PCOS patients and, therefore, promote better reproductive outcomes. These results suggest that in PCOS patients, metformin may act directly at the endometrial level and decrease insulin resistance condition by increasing the expression of GLUT4 and, in this way, indirectly restore endometrial function.
  
  
  BACKGROUND
  This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (grant number 1095127 to M.V.). None of the authors has any conflict of interest to declare.
authors.affiliation: Laboratory of Endocrinology and Reproductive Biology, University of Chile Clinical Hospital, Santos Dumont # 999, Independencia, Santiago, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Carvajal
authors.forename: Carlos
authors.initials: C
authors.lastname: Rosas
authors.forename: Karla
authors.initials: K
authors.lastname: Kohan
authors.forename: Fernando
authors.initials: F
authors.lastname: Gabler
authors.forename: David
authors.initials: D
authors.lastname: Vantman
authors.forename: Carmen
authors.initials: C
authors.lastname: Romero
authors.forename: Margarita
authors.initials: M
authors.lastname: Vega
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000328:Adult; D016022:Case-Control Studies; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D051275:Glucose Transporter Type 4 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation; D011085:Polycystic Ovary Syndrome / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D051275:Glucose Transporter Type 4; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; C495692:SLC2A4 protein, human; D008687:Metformin; D055372:AMP-Activated Protein Kinases
keywords: Glut4; PCOS; endometria; insulin resistance; metformin