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Hum. Reprod. Advance Access published online on July 21, 2005
Human Reproduction, doi:10.1093/humrep/dei205
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© The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
Received February 27, 2005
Revised May 17, 2005
Accepted June 16, 2005

Article

Polymorphisms in the insulin receptor substrate-1 (IRS-1) gene and the insulin receptor substrate-2 (IRS-2) gene influence glucose homeostasis and body mass index in women with polycystic ovary syndrome and non-hyperandrogenic controls

Gemma Villuendas 1, José I. Botella-Carretero 1, Belén Roldán 2, José Sancho 2, Héctor F. Escobar-Morreale 2*, and José L. San Millán 3

1 Department of Endocrinology, Hospital Ramón y Cajal, Madrid, Spain; These authors contributed equally to this work
2 Department of Endocrinology, Hospital Ramón y Cajal, Madrid, Spain
3 Department of Molecular Genetics, Hospital Ramón y Cajal, Madrid, Spain

* To whom correspondence should be addressed.
Héctor F. Escobar-Morreale, E-mail: hescobarm.hrc{at}salud.madrid.org


  Abstract

BACKGROUND: We aimed to evaluate the influence of the Gly972Arg variant of the insulin receptor substrate-1 gene (IRS-1) and the Gly1057Asp variant in IRS-2 on insulin resistance and glucose tolerance in women with polycystic ovary syndrome (PCOS) and healthy controls. METHODS: Genotypes, allelic frequencies, indexes of insulin resistance, glucose tolerance and hormone profiles were studied in a large sample of Spanish PCOS (n = 103) women compared with a control group (n = 48) of healthy women matched for body mass index. RESULTS: No differences in genotype or allelic frequencies were found between PCOS patients and healthy controls. When considering control subjects and PCOS patients as a whole, IRS-1 Arg972 carriers also presented with increased fasting insulin (133 ± 60 versus 95 ± 67 pmol/l, P = 0.008) and insulin resistance measured by homeostasis model assessment (4.3 ± 2.1 versus 3.1 ± 2.4, P = 0.009) compared with subjects homozygous for Gly972 alleles. These differences were even higher when restricting the analysis to PCOS patients. Subjects homozygous for the Gly1057 allele of IRS-2 presented with increased 60 and 90 min oral glucose tolerance test (OGTT) glucose levels compared with carriers of one or two Asp1057 alleles (7.9 ± 2.1 versus 7.1 ± 2.1 mmol/l, P = 0.042 and 7.0 ± 2.1 versus 6.0 ± 1.8 mmol/l, P = 0.014), and a similar tendency was observed for 120 min OGTT glucose levels. CONCLUSIONS: The Gly972Arg in IRS-1 and Gly1057Asp in IRS-2 polymorphisms influence glucose homeostasis in premenopausal women, but are not associated with PCOS.

Keywords: insulin resistance/insulin-receptor substrate/polycystic ovary syndrome/polymorphisms.
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