Glucose Meatbolism in the Human Ovary

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DESCRIPTION (provided by applicant): GLUT4 is the main insulin responsive glucose transporter in adipose and muscle which plays an important role in regulating glucose metabolism. While not sensitive to regulation by sex steroids, GLUT4 is commonly decreased in insulin resistant states. GLUTx1, also known as GLUT8, is a recently discovered glucose transporter that appears to be sex steroid regulated. It is expressed in human ovary and inhibited by sex steroids in human testis. These results suggest a sex steroid regulation of GLUT8 expression and a possible involvement of GLUT8 in the provision of glucose required for metabolic processes and DNA synthesis in germ cells. Glucose transport activity, could be an important determinant of metabolic as well as reproductive function in women. Alterations in peripheral as well as ovarian glucose transporters could be directly related to insulin resistance and perhaps to reproductive dysfunction. The relative expression of peripheral and ovarian GLUT4 and GLUT8 in women with Polycystic Ovarian Syndrome (PCOS) and normally cycling women has only partially been characterized. Alterations of GLUT8 and GLUT4 could provide insight into the pathophysiology of PCOS. To clarify the role of glucose transporters (e.g. GLUT8 and GLUT4) in normal and PCOS ovaries, the following Specific Aims are proposed. Aim 1 will examine the regulation of glucose transport and GLUT8 and GLUT4 expression/localization in a steroid-producing cell line to test the hypothesis that GLUT8, and not GLUT4, is sex steroid regulated within the ovary. Novel human ovarian theca-like and granulosa-like cell lines (HOTT and HGL-5 cells, respectively) will be used. Additionally, the ability of rosaglitazone (insulin sensitizer) to improve glucose uptake and transporter expression/localization in these cells will be assessed. Aim 2 will determine the expression and cellular localization of glucose transporters in normal human ovary. Aim 3, concurrent with Aim 2, will test the hypothesis that the ovarian expression of GLUT8 and GLUT4 is decreased in women with PCOS relative to normally cycling age- and BMI-matched controls. Aims 2 and 3 will be carried out by a prospective, case-control study of women with PCOS undergoing ovarian drilling/wedge resection for fertility and a group of normally cycling women undergoing elective tubal sterilization. Immunohistochemistry, immunoblots and RT-PCR/real time PCR will be used to determine the expression and cellular localization of GLUT8 and GLUT4 in different tissues. The proposed studies are expected to provide mechanistic insight into the regulation of glucose transport within the ovary in women, an area that has been essentially unexplored. These observations are hoped to have relevance for understanding of basic reproductive physiology and the mechanism of reproductive dysfunction in PCOS.