title: Advanced glycation end-products and insulin signaling in granulosa cells.
abstract: Advanced glycation end-products (AGEs) may interfere with insulin intracellular signaling and glucose transport in human granulosa cells, potentially affecting ovarian function, follicular growth, linked with diminished fertility. The potential interaction of AGEs with insulin signaling pathways and glucose transport was investigated in human granulosa KGN cells. KGN cells were cultured with variable concentrations of human glycated albumin (HGA, 50-200 µg/mL) or insulin (100 ng/mL). Combined treatments of KGN cells with insulin (100 ng/mL) and HGA (200 µg/mL) were also performed. p-AKT levels and glucose transporter type 4 (Glut-4) translocation analysis were performed by Western blot. Phosphatidylinositol-3-kinase (PI3K)-specific signaling was checked by using the PI3K-inhibitor, LY294002. p-AKT levels were significantly increased following insulin treatment compared to basal levels or HGA exposure. This insulin-mediated AKT-phosphorylation was PI3K-specific and it was inhibited after combined treatment of insulin and HGA. Furthermore, Glut-4 translocation from the cytoplasm to the membrane compartments of KGN cells was remarkably reduced after the combined treatment of insulin and HGA. The present findings support that AGEs interfere with insulin signaling in granulosa cells and prevent Glut-4 membrane translocation suggesting that intra ovarian AGEs accumulation, from endogenous or exogenous sources, may contribute to the pathophysiology of states characterized with anovulation and insulin resistance such as polycystic ovary syndrome.
authors.affiliation: Endocrine Unit, Internal Medicine, University of Athens Medical School, Athens 11527, Greece e.diamanti.kandarakis@gmail.com.
authors.forename: Evanthia
authors.initials: E
authors.lastname: Diamanti-Kandarakis
authors.affiliation: Department of Experimental Physiology, University of Athens Medical School, Athens 11527, Greece Department of Clinical Pathobiochemistry, Dresden University of Technology, Dresden, 01307, Germany.
authors.forename: Antonios
authors.initials: A
authors.lastname: Chatzigeorgiou
authors.affiliation: Department of Experimental Physiology, University of Athens Medical School, Athens 11527, Greece.
authors.forename: Efstathia
authors.initials: E
authors.lastname: Papageorgiou
authors.affiliation: Endocrine Unit, Internal Medicine, University of Athens Medical School, Athens 11527, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Koundouras
authors.affiliation: Department of Experimental Physiology, University of Athens Medical School, Athens 11527, Greece.
authors.forename: Michael
authors.initials: M
authors.lastname: Koutsilieris
mesh_terms: D001692:Biological Transport; D015153:Blotting, Western; D002460:Cell Line; D005260:Female; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000502:physiology*; D006107:Granulosa Cells / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012709:Serum Albumin / Q000494:pharmacology; D015398:Signal Transduction; D000093423:Glycated Serum Albumin
chemical_list: D051275:Glucose Transporter Type 4; D017127:Glycation End Products, Advanced; D007328:Insulin; C495692:SLC2A4 protein, human; D012709:Serum Albumin; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; D000093423:Glycated Serum Albumin
keywords: Glucose transporter type 4; granulosa. polycystic ovary syndrome; insulin resistance; insulin signaling