Overexpression of the phosphoprotein enriched in diabetes gene product (Ped/pea-15) in women with polycystic ovary syndrome
Silvia Savastano
Department of Molecular and Clinical Endocrinology and Oncology, University ‘Federico II’, Naples, Italy,
Search for more papers by this authorFrancesco Orio Jr
Department of Molecular and Clinical Endocrinology and Oncology, University ‘Federico II’, Naples, Italy,
Search for more papers by this authorStefano Palomba
Department of Obstetrics and Gynecology, University ‘Magna Graecia’, Catanzaro, Italy,
Search for more papers by this authorTeresa Cascella
Department of Molecular and Clinical Endocrinology and Oncology, University ‘Federico II’, Naples, Italy,
Search for more papers by this authorFrancesco Manguso
Department of Clinical and Experimental Medicine, Gastroenterology Unit and
Search for more papers by this authorGelsy Arianna Lupoli
C.N.R. Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, Department of Cellular and Molecular Biology and Pathology, University ‘Federico II’, Naples, Italy
Search for more papers by this authorPietro Formisano
C.N.R. Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, Department of Cellular and Molecular Biology and Pathology, University ‘Federico II’, Naples, Italy
Search for more papers by this authorGaetano Lombardi
Department of Molecular and Clinical Endocrinology and Oncology, University ‘Federico II’, Naples, Italy,
Search for more papers by this authorAnnamaria Colao
Department of Molecular and Clinical Endocrinology and Oncology, University ‘Federico II’, Naples, Italy,
Search for more papers by this authorFrancesco Beguinot
C.N.R. Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, Department of Cellular and Molecular Biology and Pathology, University ‘Federico II’, Naples, Italy
Search for more papers by this authorRossella Valentino
C.N.R. Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, Department of Cellular and Molecular Biology and Pathology, University ‘Federico II’, Naples, Italy
Search for more papers by this authorSilvia Savastano
Department of Molecular and Clinical Endocrinology and Oncology, University ‘Federico II’, Naples, Italy,
Search for more papers by this authorFrancesco Orio Jr
Department of Molecular and Clinical Endocrinology and Oncology, University ‘Federico II’, Naples, Italy,
Search for more papers by this authorStefano Palomba
Department of Obstetrics and Gynecology, University ‘Magna Graecia’, Catanzaro, Italy,
Search for more papers by this authorTeresa Cascella
Department of Molecular and Clinical Endocrinology and Oncology, University ‘Federico II’, Naples, Italy,
Search for more papers by this authorFrancesco Manguso
Department of Clinical and Experimental Medicine, Gastroenterology Unit and
Search for more papers by this authorGelsy Arianna Lupoli
C.N.R. Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, Department of Cellular and Molecular Biology and Pathology, University ‘Federico II’, Naples, Italy
Search for more papers by this authorPietro Formisano
C.N.R. Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, Department of Cellular and Molecular Biology and Pathology, University ‘Federico II’, Naples, Italy
Search for more papers by this authorGaetano Lombardi
Department of Molecular and Clinical Endocrinology and Oncology, University ‘Federico II’, Naples, Italy,
Search for more papers by this authorAnnamaria Colao
Department of Molecular and Clinical Endocrinology and Oncology, University ‘Federico II’, Naples, Italy,
Search for more papers by this authorFrancesco Beguinot
C.N.R. Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, Department of Cellular and Molecular Biology and Pathology, University ‘Federico II’, Naples, Italy
Search for more papers by this authorRossella Valentino
C.N.R. Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, Department of Cellular and Molecular Biology and Pathology, University ‘Federico II’, Naples, Italy
Search for more papers by this authorSilvia Savastano and Francesco Orio Jr are first authors of the manuscript as they equally contributed to the article.
Summary
Objective To evaluate Ped/pea-15 (phosphoprotein enriched in diabetes) expression in polycystic ovary syndrome (PCOS) women.
Design and patients Thirty PCOS women were studied and compared with other 30 age- and body mass index (BMI)-matched women, considered as the control group. Both patients and controls were divided according to BMI. All subjects underwent endocrine and metabolic investigation and Ped/pea-15 expression was evaluated by western blot analysis. Insulin resistance was assessed by HOMA model and insulin sensitivity index (ISI) composite.
Results Insulin resistance, evaluated by HOMA-R and ISI composite, was significantly higher in PCOS women and in obese controls than in normal weight controls. Ped/pea-15 expression (%) was higher in PCOS women than in controls (440·4 ± 220·7 vs. 163·0 ± 45·5; P < 0·001; range 145·5–987% and 97–281%, respectively), and was positively correlated with insulin, BMI, total testosterone, HOMA index, and family history (P < 0·001). In patients with PCOS univariate analysis of variance showed no effect of BMI variation (P = 0·13) on Ped/pea-15 expression levels. On multiple linear regression analysis, the major determinants of Ped/pea-15 overexpression were family history, insulin, and PCOS status independent of BMI.
Conclusion These preliminary data (1) highlight the overexpression of Ped/pea-15 in PCOS compared to normal controls, independent of obesity; (2) suggest that Ped/pea-15 overexpression might be an early component of the metabolic syndrome in PCOS; and (3) support the hypothesis that Ped/pea-15 represents a possible useful tool to assess the presence of a genetic condition associated with insulin resistance in PCOS.
References
- 1 Condorelli, G., Vigliotta, G., Iavarone, C., Caruso, M., Tocchetti, C.G., Andreozzi, F., Cafieri, A., Tecce, M.F., Formisano, P., Beguinot, L. & Beguinot, F. (1998) PED/PEA-15 gene controls glucose transport and is overexpressed in type 2 diabetes mellitus. The EMBO Journal, 17, 3858–3866.
- 2 Condorelli, G., Vigliotta, G., Trencia, A., Maitan, M.A., Caruso, M., Miele, C., Oriente, F., Santopietro, S., Formisano, P. & Beguinot, F. (2001) Protein kinase C (PKC)-α activation inhibits PKC-ζ and mediates the action of PED/PEA-15 on glucose transport in the L6 skeletal muscle cells. Diabetes, 50, 1244–1252.
- 3 Vigliotta, G., Miele, C., Santopietro, S., Portella, G., Perfetti, A., Maitan, M.A., Cassese, A., Oriente, F., Trencia, A., Fiory, F., Romano, C., Tiveron, C., Tatangelo, L., Troncone, G., Formisano, P. & Beguinot, F. (2004) Overexpression of the ped/pea-15 gene causes diabetes by impairing glucose-stimulated insulin secretion in addition to insulin action. Molecular and Cellullar Biology, 24, 5005–5015.
- 4 Valentino, R., Autuori, E., Riccardi, G., Vaccaro, O., Trencia, A., Fiory, F., Alberobello, A.T., Miele, C., Formisano, F. & Beguinot, F. (2003) PED expression in white blood cells in type 2 diabetic patients. Journal of Endocrinological Investigation, 26, 111.
- 5 Valentino, R., Lupoli, G.A., Raciti, G.A., Oriente, F., Marinaro, E., Della Valle, E., Salomone, M., Riccardi, G., Vaccaro, O., Donnarumma, G., Sesti, G., Hribal, M.L., Cardellini, M., Miele, C., Formisano, P. & Beguinot, F. (2006) The PEA15 gene is overexpressed and related to insulin resistance in healthy first-degree relatives of patients with type 2 diabetes. Diabetologia, 49, 3058–3066.
- 6 Dunaif, A. (1997) Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocrine Reviews, 18, 774–800.
- 7 Ehrmann, D.A. (2000) Glucose intolerance in the polycystic ovary syndrome: role of the pancreatic beta-cell. Journal of Pediatric Endocrinology & Metabolism, 13, 1299–1301.
- 8
Nestler, J.E. (2003) Insulin resistance syndrome and the polycystic ovary syndrome.
Endocrine Practice, 8, 86–89.
10.4158/EP.9.S2.86 Google Scholar
- 9 Yildiz, B.O. (2004) Assessment of glucose intolerance and insulin sensitivity in polycystic ovary syndrome. Reproductive Biomedicine Online, 8, 649–656.
- 10 Ehrmann, D.A. (2005) Polycystic ovary syndrome. New England Journal of Medicine, 352, 1223–1236.
- 11 Ehrmann, D.A., Barnes, R.B., Rosenfield, R.L., Cavaghan, M.K. & Imperial, J. (1999) Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care, 22, 141–146.
- 12 Legro, R.S., Kunselman, A.R., Dodson, W.C. & Dunaif, A. (1999) Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. Journal of Clinical Endocrinology and Metabolism, 84, 165–169.
- 13 Conn, J.J., Jacobs, H.S. & Conway, G.S. (2000) The prevalence of polycystic ovaries in women with type 2 diabetes mellitus. Clinical Endocrinology, 52, 81–86.
- 14 Ovalle, F. & Azziz, R. (2002) Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mellitus. Fertility and Sterility, 77, 1095–1105.
- 15 Gambineri, A., Pelusi, C., Manicardi, E., Vicennati, V., Cacciari, M., Morselli-Labate, A.M., Pagotto, U. & Pasquali, R. (2004) Glucose intolerance in a large cohort of Mediterranean women with polycystic ovary sindrome. Phenotype and associated factors. Diabetes, 53, 2353–2358.
- 16 Palmert, M.R., Gordon, C.M., Kartashov, A.I., Legro, R.S., Emans, S.J. & Dunaif, A. (2002) Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism, 87, 1017–1023.
- 17 Azziz, R., Woods, K.S., Reyna, R., Key, T.J., Knocknenhauer, E.S. & Yildiz, B.O. (2004) The prevalence and features of the polycystic ovary syndrome in an unselected population. Journal of Clinical Endocrinology and Metabolism, 89, 2745–2749.
- 18 Dunaif, A., Segal, K.R., Futterweit, W. & Dubrjansky, A. (1989) Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes, 38, 1165–1174.
- 19 Dunaif, A., Wu, X., Lee, A. & Diamanti-Kandarakis, E. (2001) Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). American Journal of Physiology – Endocrinology and Metabolism, 281, E392–E399.
- 20 Marsden, P.J., Murdoch, A.P. & Taylor, R. (2001) Tissue insulin sensitivity and body weight in polycystic ovary syndrome. Clinical Endocrinology, 55, 191–199.
- 21 The Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Human Reproduction, 19, 41–47.
- 22 Barbieri, R.L. (1999) Infertility. In: S.S.C. Yen, R.B. Yaffe, R.L. Barbieri, eds. Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 4th edn. W.B. Saunders, Philadelphia, 562–593.
- 23 Ferriman, D. & Gallwey, J.D. (1961) Clinical assessment of body hair growth in women. Journal of Clinical Endocrinology and Metabolism, 21, 1440–1447.
- 24 The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (1997) Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care, 20, 1183–1197.
- 25 Orio, F. Jr, Palomba, S., Spinelli, L., Cascella, T., Tauchmanovà, L., Zullo, F., Lombardi, G. & Colao, A. (2004a) The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study. Journal of Clinical Endocrinology and Metabolism, 89, 3696–3701.
- 26 Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F. & Turner, R.C. (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28, 412–419.
- 27 Matsuda, M. & DeFronzo, R.A. (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing. Diabetes Care, 22, 1462–1470.
- 28 Palomba, S., Affinito, P., Di Carlo, C., Bifulco, G. & Nappi, C. (1999) Long-term administration of tibolone plus gonadotropin-releasing hormone agonist for the treatment of uterine leiomyomas: effectiveness and effects on vasomotor symptoms, bone mass, and lipid profiles. Fertility and Sterility, 72, 889–895.
- 29 Friedewald, W.T., Levy, R.I. & Fredrickson, D.S. (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical Chemstry, 18, 499–502.
- 30 Araujo, H., Danzinger, N., Cordier, J., Glowinski, J. & Chneiweiss, H. (1993) Characterization of PEA-15, a major substrate for protein kinase C in astrocytes. Journal of Biological Chemistry, 268, 5911–5920.
- 31 Yildiz, B.O., Yarali, H., Oguz, H. & Bayraktar, M. (2003) Glucose intolerance, insulin resistance, and hyperandrogenemia in first degree relatives of women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism, 88, 2031–2036.
- 32 Cibula, D. (2004) Is insulin resistance an essential component of PCOS?: the influence of confounding factors. Human Reproduction, 19, 757–759.
- 33 Orio, F. Jr, Palomba, S., De Simone, B., Di Biase, S., Russo, T., Labella, D., Zullo, F., Lombardi, G. & Colao, A. (2004b) Early impairment of endothelial structure and function in young normal-weight women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism, 89, 4588–4593.
- 34 Shulman, G.I. (2000) Cellular mechanisms of insulin resistance. Journal of Clinical Investigations, 106, 171–176.
- 35 Ehrmann, D.A. (2004) Genetic contribution to glucose intolerance in polycystic ovary syndrome. Reproductive Biomedicine Online, 9, 28–34.
- 36 Nestler, J.E. & Jakubowicz, D.J. (1997) Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. Journal of Clinical Endocrinology and Metabolism, 82, 524–530.
- 37 Korhonen, S., Hippelainen, M., Vanhala, M., Heinonen, S. & Niskanen, L. (2003) The androgenic sex hormone profile is an essential feature of metabolic syndrome in premenopausal women: a controlled community-based study. Fertility and Sterility, 79, 1327–1334.
- 38 Pasquali, R. & Gambineri, A. (2006) Insulin-sensitizing agents in polycystic ovary syndrome. European Journal of Endocrinology, 154, 763–775.
- 39 Sir-Petermann, T., Angel, B., Maliqueo, M., Carvajal, F., Santos, J.L. & Perez-Bravo, F. (2002) Prevalence of type 2 diabetes mellitus and insulin resistance in parents of women with polycystic ovary syndrome. Diabetologia, 45, 959–964.
- 40 Legro, R.S., Castracane, V.D. & Kauffman, R.P. (2004) Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls. Obstetrical and Gynecological Survey, 59, 141–154.
- 41 Legro, R.S. (1999) Polycystic ovary syndrome. Phenotype to genotype. Endocrinology and Metabolism Clinics of North America, 28, 379–396.
- 42 Glintborg, D., Andersen, M., Hagen, C., Frystyk, J., Hulstrom, V., Flyvbjerg, A. & Hermann, A.P. (2006) Evaluation of metabolic risk markers in polycystic ovary syndrome (PCOS). Adiponectin, ghrelin, leptin, and body composition in hirsute PCOS patients and controls. European Journal of Endocrinology, 155, 337–345.