Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2012; 44(11): 810-813
DOI: 10.1055/s-0032-1321817

Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Insulin Resistant Phenotype of Polycystic Ovary Syndrome does not Seem to be Caused by Variation in FTO

E. Hatziagelaki^*

¹2nd Department of Internal Medicine, Research Institute and Diabetes Center, Athens University Medical School, “Attikon” University Hospital, Athens, Greece

,

R. Wagner^*

²Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Eberhard Karls University, Tübingen, Germany

,

K. Kantartzis

²Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Eberhard Karls University, Tübingen, Germany

³Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (Paul Langerhans Institute Tübingen), Tübingen, Germany

,

M. Heni

²Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Eberhard Karls University, Tübingen, Germany

,

K. Linder

²Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Eberhard Karls University, Tübingen, Germany

,

C. Ketterer

²Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Eberhard Karls University, Tübingen, Germany

,

F. Machicao

²Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Eberhard Karls University, Tübingen, Germany

³Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (Paul Langerhans Institute Tübingen), Tübingen, Germany

,

N. Stefan

²Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Eberhard Karls University, Tübingen, Germany

³Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (Paul Langerhans Institute Tübingen), Tübingen, Germany

,

H. Staiger

²Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Eberhard Karls University, Tübingen, Germany

³Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (Paul Langerhans Institute Tübingen), Tübingen, Germany

,

H. U. Häring

²Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Eberhard Karls University, Tübingen, Germany

³Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (Paul Langerhans Institute Tübingen), Tübingen, Germany

,

A. Fritsche

²Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Eberhard Karls University, Tübingen, Germany

³Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (Paul Langerhans Institute Tübingen), Tübingen, Germany

⁴Department of Internal Medicine, Division of Nutritional and Preventive Medicine, University Hospital Tübingen, Tübingen, Germany

› Author Affiliations

Abstract

Genetic variation in the FTO gene is associated with increased body weight and reduced insulin sensitivity. We investigated whether genetic variation in FTO is associated with polycystic ovary syndrome (PCOS), a condition also characterized by insulin resistance. Furthermore, we tested whether insulin resistance is specifically associated with genetic variation in FTO in women with PCOS. Sixty-two nondiabetic patients with PCOS defined by the Rotterdam criteria were compared to BMI and age-matched women. Each PCOS case was matched to 2 controls. All participants underwent an oral glucose tolerance test and were genotyped for the single nucleotide polymorphism rs8050136 in the FTO gene. There was no difference in the frequency of FTO genotypes between the PCOS and the non-PCOS groups. In non-PCOS participants, genetic variation in FTO is associated with insulin sensitivity (p=0.03). This association remained significant after adjustment for age and/or BMI (p<= 0.03). In subjects with PCOS, however, FTO did not associate with insulin sensitivity (p=0.67). Genetic variation in FTO does not have an impact on insulin sensitivity in women with PCOS and is therefore not involved in the pathogenesis of the insulin resistant phenotype seen in patients with PCOS.

Key words

Key words

FTO - polycystic ovary syndrome (PCOS) - insulin resistance - matched case-control study

References
1 Haupt A, Thamer C, Staiger H, Tschritter O, Kirchhoff K, Machicao F, Häring H-U, Stefan N, Fritsche A. Variation in the FTO gene influences food intake but not energy expenditure. Exp Clin Endocrinol Diabetes 2009; 117: 194-197
2 Haupt A, Thamer C, Machann J, Kirchhoff K, Stefan N, Tschritter O, Machicao F, Schick F, Häring H-U, Fritsche A. Impact of variation in the FTO gene on whole body fat distribution, ectopic fat, and weight loss. Obesity (Silver Spring) 2008; 16: 1969-1972
3 Barber TM, Bennett AJ, Groves CJ, Sovio U, Ruokonen A, Martikainen H, Pouta A, Hartikainen A-L, Elliott P, Lindgren CM, Freathy RM, Koch K, Ouwehand WH, Karpe F, Conway GS, Wass JAH, Järvelin M-R, Franks S, McCarthy MI. Association of variants in the fat mass and obesity associated (FTO) gene with polycystic ovary syndrome. Diabetologia 2008; 51: 1153-1158
4 Ewens KG, Jones MR, Ankener W, Stewart DR, Urbanek M, Dunaif A, Legro RS, Chua A, Azziz R, Spielman RS, Goodarzi MO, Strauss 3rd JF. FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome. PLoS ONE 2011; 6: e16390
5 Tschritter O, Preissl H, Yokoyama Y, Machicao F, Häring H-U, Fritsche A. Variation in the FTO gene locus is associated with cerebrocortical insulin resistance in humans. Diabetologia 2007; 50: 2602-2603
6 Grunnet LG, Brøns C, Jacobsen S, Nilsson E, Astrup A, Hansen T, Pedersen O, Poulsen P, Quistorff B, Vaag A. Increased recovery rates of phosphocreatine and inorganic phosphate after isometric contraction in oxidative muscle fibers and elevated hepatic insulin resistance in homozygous carriers of the A-allele of FTO rs9939609. J Clin Endocrinol Metab 2009; 94: 596-602
7 Kring SII, Holst C, Zimmermann E, Jess T, Berentzen T, Toubro S, Hansen T, Astrup A, Pedersen O, Sørensen TIA. FTO gene associated fatness in relation to body fat distribution and metabolic traits throughout a broad range of fatness. PLoS ONE 2008; 3: e2958
8 Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999; 22: 141-146
9 Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab 2006; 91: 2100-2104
10 Chen Z-J, Zhao H, He L, Shi Y, Qin Y, Shi Y, Li Z, You L, Zhao J, Liu J, Liang X, Zhao X, Zhao J, Sun Y, Zhang B, Jiang H, Zhao D, Bian Y, Gao X, Geng L, Li Y, Zhu D, Sun X, Xu J, Hao C, Ren C, Zhang Y, Chen S, Zhang W, Yang A, Yan J, Li Y, Ma J, Zhao Y. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet 2011; 43: 55-59
11 Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 2011; 7: 219-231
12 Nestler JE, Jakubowicz DJ, de Vargas AF, Brik C, Quintero N, Medina F. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 1998; 83: 2001-2005
13 Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, Clore JN, Blackard WG. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 1991; 72: 83-89
14 Stefan N, Kantartzis K, Machann J, Schick F, Thamer C, Rittig K, Balletshofer B, Machicao F, Fritsche A, Häring H-U. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 2008; 168: 1609-1616
15 Kantartzis K, Machann J, Schick F, Rittig K, Machicao F, Fritsche A, Häring H-U, Stefan N. Effects of a lifestyle intervention in metabolically benign and malign obesity. Diabetologia 2011; 54: 864-868
16 Yildiz BO, Knochenhauer ES, Azziz R. Impact of obesity on the risk for polycystic ovary syndrome. J Clin Endocrinol Metab 2008; 93: 162-168
17 Diamanti-Kandarakis E, Kouli CR, Bergiele AT, Filandra FA, Tsianateli TC, Spina GG, Zapanti ED, Bartzis MI. A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 1999; 84: 4006-4011
18 Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 2004; 89: 2745-2749
19 Asunción M, Calvo RM, San Millán JL, Sancho J, Avila S, Escobar-Morreale HF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000; 85: 2434-2438
20 Yan Q, Hong J, Gu W, Zhang Y, Liu Q, Su Y, Zhang Y, Li X, Cui B, Ning G. Association of the common rs9939609 variant of FTO gene with polycystic ovary syndrome in Chinese women. Endocrine 2009; 36: 377-382
21 Attaoua R, Ait El Mkadem S, Radian S, Fica S, Hanzu F, Albu A, Gheorghiu M, Coculescu M, Grigorescu F. FTO gene associates to metabolic syndrome in women with polycystic ovary syndrome. Biochem Biophys Res Commun 2008; 373: 230-234
22 Haap M, Machicao F, Stefan N, Thamer C, Tschritter O, Schnuck F, Wallwiener D, Stumvoll M, Häring H-U, Fritsche A. Genetic determinants of insulin action in polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 2005; 113: 275-281
23 Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: 41-47
24 Matsuda M. Measuring and estimating insulin resistance in clinical and research settings. Nutr Metab Cardiovasc Dis 2010; 20: 79-86
25 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419
26 Kim JJ, Choi YM, Cho YM, Hong MA, Chae SJ, Hwang KR, Hwang SS, Yoon SH, Moon SY. Polycystic ovary syndrome is not associated with polymorphisms of the TCF7L2, CDKAL1, HHEX, KCNJ11, FTO and SLC30A8 genes. Clinical Endocrinology 2012; [cited 2012 Apr 16]; Available from http://www.ncbi.nlm.nih.gov/pubmed/22443257
27 Saxena R, Welt CK. Polycystic ovary syndrome is not associated with genetic variants that mark risk of type 2 diabetes. Acta Diabetologica 2012; [cited 2012 Apr 16]; Available from http://www.ncbi.nlm.nih.gov/pubmed/22389004
28 Kowalska I, Malecki MT, Straczkowski M, Skupien J, Karczewska-Kupczewska M, Nikolajuk A, Szopa M, Adamska A, Wawrusiewicz-Kurylonek N, Wołczynski S, Sieradzki J, Gorska M. The FTO gene modifies weight, fat mass and insulin sensitivity in women with polycystic ovary syndrome, where its role may be larger than in other phenotypes. Diabetes Metab 2009; 35: 328-331
29 Tan S, Scherag A, Janssen OE, Hahn S, Lahner H, Dietz T, Scherag S, Grallert H, Vogel CIG, Kimmig R, Illig T, Mann K, Hebebrand J, Hinney A. Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS). BMC Med Genet 2010; 11: 12
30 March WA, Moore VM, Willson KJ, Phillips DIW, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010; 25: 544-551