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Exp Clin Endocrinol Diabetes 2005; 113(5): 275-281
DOI: 10.1055/s-2005-837665
Article

J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Genetic Determinants of Insulin Action in Polycystic Ovary Syndrome

M. Haap1 , F. Machicao1 , N. Stefan1 , C. Thamer1 , O. Tschritter1 , F. Schnuck1 , D. Wallwiener2 , M. Stumvoll1 , 3 , H.-U. Häring1 , A. Fritsche1
  • 1Department of Endocrinology, Metabolism and Clinical Chemistry, University of Tübingen, Germany
  • 2Department of Department of Obstetrics and Gynecology, University of Tübingen, Germany
  • 3III. Medical Department, University of Leipzig, Germany
Further Information

Publication History

Received: August 30, 2004 First decision: November 15, 2004

Accepted: January 20, 2005

Publication Date:
30 May 2005 (online)

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Abstract

Introduction: Insulin resistance is associated with both type 2 diabetes (T2 D) and polycystic ovary syndrome (PCOS). There is an association of T2 D with several polymorphisms in candidate genes related to insulin resistance. However, there is limited information about the association of these polymorphisms with PCOS. Methods: 57 non-diabetic women with PCOS and a control group of 567 healthy non-diabetic women underwent an oral glucose tolerance test (OGTT). They were genotyped for the polymorphisms Gly972Arg in IRS-1, Gly1057Asp in IRS-2, SNP 43, 44, and 45 in CAPN10, Pro12Ala in PPARγ2, C-512 T in FOXC2, and T45 G in adiponectin. Results: Women with PCOS had higher 2-h blood glucose levels (6.5 ± 0.2 vs. 6.0 ± 0.06 mmol/l, p = 0.03) compared to control women, higher fasting insulin (79 ± 7 vs. 53 ± 2 pmol/l, p = 0.02), and a lower insulin sensitivity estimated from the OGTT (12.4 ± 1.1 vs. 19.1 ± 0.5 U, p = 0.0001). More homozygous G allele carriers of the T45 G polymorphism in the adiponectin gene were found in women with PCOS compared to controls (13.2 % vs. 2.6 %, p = 0.008). In women with PCOS, G-allele carriers had lower fasting insulin levels than TT carriers (61 ± 9 vs. 88 ± 10, p = 0.02) in contrast to controls (p = 0.03 for interaction genotype × PCOS). The other polymorphisms were distributed equally among women with PCOS and controls (all p > 0.5). Summary: We found a higher prevalence of the T45 G polymorphism in the adiponectin gene in women with PCOS compared to controls. This was not associated with a more insulin resistant phenotype in PCOS, however. Other frequent polymorphisms in genes related to insulin resistance and type 2 diabetes showed no association with PCOS.

Key words

Polycystic ovary syndrome - polymorphism - insulin resistance - linkage - genetics

References

  • 1 The Rotterdam consensus workshop . Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.  Fertil Steril. 2004;  81 19-25
    PubMedGoogle Scholar
  • 2 Chandran M, Phillips S A, Ciaraldi T, Henry R R. Adiponectin: more than just another fat cell hormone?.  Diabetes Care. 2003;  26 2442-2450
    CrossrefPubMedGoogle Scholar
  • 3 Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis.  Endocr Rev. 1997;  18 774-800
    CrossrefPubMedGoogle Scholar
  • 4 Ehrmann D A, Tang X, Yoshiuchi I, Cox N J, Bell G I. Relationship of insulin receptor substrate-1 and -2 genotypes to phenotypic features of polycystic ovary syndrome.  J Clin Endocrinol Metab. 2002 a;  87 4297-4300
    CrossrefPubMedGoogle Scholar
  • 5 Ehrmann D A, Tang X, Yoshiuchi I, Cox N J, Bell G I. Relationship of insulin receptor substrate-1 and -2 genotypes to phenotypic features of polycystic ovary syndrome.  J Clin Endocrinol Metab. 2002 b;  87 4297-4300
    CrossrefPubMedGoogle Scholar
  • 6 El Mkadem S A, Lautier C, Macari F, Molinari N, Lefebvre P, Renard E, Gris J C, Cros G, Daures J P, Bringer J. et al . Role of allelic variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in moderate-to-severe insulin resistance of women with polycystic ovary syndrome.  Diabetes. 2001;  50 2164-2168
    CrossrefPubMedGoogle Scholar
  • 7 Fritsche A, Machicao F, Staiger H, Haring H U, Stumvoll M. Lack of association between metabolic traits and the - 512 polymorphism in FOXC2 in German people with normal glucose tolerance.  Diabetologia. 2004;  47 756-757
    PubMedGoogle Scholar
  • 8 Fritsche A, Madaus A, Renn W, Tschritter O, Teigeler A, Weisser M, Maerker E, Machicao F, Haring H, Stumvoll M. The prevalent Gly1057Asp polymorphism in the insulin receptor substrate-2 gene is not associated with impaired insulin secretion.  J Clin Endocrinol Metab. 2001;  86 4822-4825
    CrossrefPubMedGoogle Scholar
  • 9 Fumeron F, Aubert R, Siddiq A, Betoulle D, Pean F, Hadjadj S, Tichet J, Wilpart E, Chesnier M C, Balkau B. et al . Adiponectin gene polymorphisms and adiponectin levels are independently associated with the development of hyperglycemia during a 3-year period: The Epidemiologic Data on the Insulin Resistance Syndrome Prospective Study.  Diabetes. 2004;  53 1150-1157
    PubMedGoogle Scholar
  • 10 Gonzalez A, Abril E, Roca A, Aragon M J, Figueroa M J, Velarde P, Royo J L, Real L M, Ruiz A. Comment: CAPN10 alleles are associated with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2002;  87 3971-3976
    CrossrefPubMedGoogle Scholar
  • 11 Haddad L, Evans J C, Gharani N, Robertson C, Rush K, Wiltshire S, Frayling T M, Wilkin T J, Demaine A, Millward A. et al . Variation within the type 2 diabetes susceptibility gene calpain-10 and polycystic ovary syndrome.  J Clin Endocrinol Metab. 2002;  87 2606-2610
    CrossrefPubMedGoogle Scholar
  • 12 Hara K, Boutin P, Mori Y, Tobe K, Dina C, Yasuda K, Yamauchi T, Otabe S, Okada T, Eto K. et al . Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population.  Diabetes. 2002 a;  51 536-540
    PubMedGoogle Scholar
  • 13 Hara M, Alcoser S Y, Qaadir A, Beiswenger K K, Cox N J, Ehrmann D A. Insulin resistance is attenuated in women with polycystic ovary syndrome with the Pro(12)Ala polymorphism in the PPARgamma gene.  J Clin Endocrinol Metab. 2002 b;  87 772-775
    CrossrefPubMedGoogle Scholar
  • 14 Horikawa Y, Oda N, Cox N J, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner T H, Mashima H, Schwarz P E. et al . Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus.  Nat Genet. 2000;  26 163-175
    Google Scholar
  • 15 Hu F B, Doria A, Li T, Meigs J B, Liu S, Memisoglu A, Hunter D, Manson J E. Genetic variation at the adiponectin locus and risk of type 2 diabetes in women.  Diabetes. 2004;  53 209-213
    PubMedGoogle Scholar
  • 16 Jellema A, Zeegers M P, Feskens E J, Dagnelie P C, Mensink R P. Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies.  Diabetologia. 2003;  46 990-995
    CrossrefPubMedGoogle Scholar
  • 17 Legro R S. Diabetes prevalence and risk factors in polycystic ovary syndrome.  Obstet Gynecol Clin North Am. 2001;  28 99-109
    CrossrefPubMedGoogle Scholar
  • 18 Legro R S, Spielman R, Urbanek M, Driscoll D, Strauss III J F, Dunaif A. Phenotype and genotype in polycystic ovary syndrome.  Recent Prog Horm Res. 1998;  53 217-256
    PubMedGoogle Scholar
  • 19 Legro R S, Strauss J F. Molecular progress in infertility: polycystic ovary syndrome.  Fertil Steril. 2002;  78 569-576
    CrossrefPubMedGoogle Scholar
  • 20 Matsuda M, DeFronzo R A. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.  Diabetes Care. 1999;  22 1462-1470
    CrossrefPubMedGoogle Scholar
  • 21 Menzaghi C, Ercolino T, Di Paola R, Berg A H, Warram J H, Scherer P E, Trischitta V, Doria A. A haplotype at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome.  Diabetes. 2002;  51 2306-2312
    PubMedGoogle Scholar
  • 22 Olefsky J M, Saltiel A R. PPAR gamma and the treatment of insulin resistance.  Trends Endocrinol Metab. 2000;  11 362-368
    CrossrefPubMedGoogle Scholar
  • 23 Orio Jr F, Palomba S, Cascella T, Milan G, Mioni R, Pagano C, Zullo F, Colao A, Lombardi G, Vettor R. Adiponectin levels in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2003;  88 2619-2623
    CrossrefPubMedGoogle Scholar
  • 24 Panidis D, Kourtis A, Farmakiotis D, Mouslech T, Rousso D, Koliakos G. Serum adiponectin levels in women with polycystic ovary syndrome.  Hum Reprod. 2003;  18 1790-1796
    CrossrefPubMedGoogle Scholar
  • 25 Panidis D, Kourtis A, Kukuvitis A, Farmakiotis D, Xita N, Georgiou I, Tsatsoulis A. Association of the T45 G polymorphism in exon 2 of the adiponectin gene with polycystic ovary syndrome: role of {Delta}4-androstenedione.  Hum Reprod. 2004;  19 1728-1733
    CrossrefPubMedGoogle Scholar
  • 26 Ridderstrale M, Carlsson E, Klannemark M, Cederberg A, Kosters C, Tornqvist H, Storgaard H, Vaag A, Enerback S, Groop L. FOXC2 mRNA Expression and a 5′untranslated region polymorphism of the gene are associated with insulin resistance.  Diabetes. 2002;  51 3554-3560
    PubMedGoogle Scholar
  • 27 Sesti G, Federici M, Hribal M L, Lauro D, Sbraccia P, Lauro R. Defects of the insulin receptor substrate (IRS) system in human metabolic disorders.  FASEB J. 2001;  15 2099-2111
    CrossrefPubMedGoogle Scholar
  • 28 Stumvoll M, Fritsche A, Madaus A, Stefan N, Weisser M, Machicao F, Haring H. Functional significance of the UCSNP-43 polymorphism in the CAPN10 gene for proinsulin processing and insulin secretion in nondiabetic Germans.  Diabetes. 2001 a;  50 2161-2163
    PubMedGoogle Scholar
  • 29 Stumvoll M, Fritsche A, Volk A, Stefan N, Madaus A, Maerker E, Teigeler A, Koch M, Machicao F, Haring H. The Gly972Arg polymorphism in the insulin receptor substrate-1 gene contributes to the variation in insulin secretion in normal glucose-tolerant humans.  Diabetes. 2001 b;  50 882-885
    PubMedGoogle Scholar
  • 30 Stumvoll M, Haring H. The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism.  Diabetes. 2002;  51 2341-2347
    PubMedGoogle Scholar
  • 31 Stumvoll M, Tschritter O, Fritsche A, Staiger H, Renn W, Weisser M, Machicao F, Haring H. Association of the T-G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity: interaction with family history of type 2 diabetes.  Diabetes. 2002 a;  51 37-41
    CrossrefPubMedGoogle Scholar
  • 32 Stumvoll M, Wahl H G, Machicao F, Haring H. Insulin sensitivity of glucose disposal and lipolysis: no influence of common genetic variants in IRS-1 and CAPN10.  Diabetologia. 2002 b;  45 651-656
    CrossrefPubMedGoogle Scholar
  • 33 Thamer C, Stumvoll M, Niess A, Tschritter O, Haap M, Becker R, Shirkavand F, Bachmann O, Rett K, Volk A. et al . Reduced skeletal muscle oxygen uptake and reduced β-cell funtion. Two early abnormalities in normal glucose tolerant offspring of patients with type 2 diabetes.  Diabetes Care. 2003;  26 2126-2132
    CrossrefPubMedGoogle Scholar
  • 35 Urbanek M, Legro R S, Driscoll D A, Azziz R, Ehrmann D A, Norman R J, Strauss III J F, Spielman R S, Dunaif A. Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin.  Proc Natl Acad Sci USA. 1999;  96 8573-8578
    CrossrefPubMedGoogle Scholar
  • 36 Vankova M, Vrbikova J, Hill M, Cinek O, Bendlova B. Association of insulin gene VNTR polymorphism with polycystic ovary syndrome.  Ann N Y Acad Sci. 2002;  967 558-565
    PubMedGoogle Scholar
  • 37 Vasseur F, Helbecque N, Dina C, Lobbens S, Delannoy V, Gaget S, Boutin P, Vaxillaire M, Lepretre F, Dupont S. et al . Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians.  Hum Mol Genet. 2002;  11 2607-2614
    CrossrefPubMedGoogle Scholar
  • 38 Waterworth D M, Bennett S T, Gharani N, McCarthy M I, Hague S, Batty S, Conway G S, White D, Todd J A, Franks S. et al . Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome.  Lancet. 1997;  349 986-990
    CrossrefPubMedGoogle Scholar
  • 39 Xita N, Georgiou I, Tsatsoulis A. The genetic basis of polycystic ovary syndrome.  Eur J Endocrinol. 2002;  147 717-725
    CrossrefPubMedGoogle Scholar
  • 40 Yang W S, Tsou P L, Lee W J, Tseng D L, Chen C L, Peng C C, Lee K C, Chen M J, Huang C J, Tai T Y. et al . Allele-specific differential expression of a common adiponectin gene polymorphism related to obesity.  J Mol Med. 2003;  81 428-434
    CrossrefPubMedGoogle Scholar

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