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
- Samira Ait El Mkadem1,
- Corinne Lautier1,
- Françoise Macari1,
- Nicolas Molinari1,
- Patrick Lefèbvre2,
- Eric Renard2,
- Jean Christophe Gris1,
- Gérard Cros1,
- Jean Pierre Daurès1,
- Jacques Bringer2,
- Morris F. White3 and
- Florin Grigorescu1
- 1Molecular Endocrinology Laboratory, Institut Universitaire de Recherche Cilnique, Montpellier, France
- 2Department of Endocrinology, Lapeyronie Hospital, Montpellier, France
- 3Joslin Diabetes Center, Boston, Massachusetts
Abstract
To assess the role of insulin receptor, insulin receptor substrate (IRS)-1, and IRS-2 genes in insulin resistance, we explored the genomic DNA in women with polycystic ovary syndrome (PCOS) and a variable degree (mean ± SE) of insulin resistance (homeostasis model assessment index for insulin resistance [HOMAIR] 3.2 ± 0.6, n = 53; control subjects 1.56 ± 0.34, n = 102) using direct sequencing. Whereas no novel mutations were found in these genes, gene-dosage effects were found on fasting insulin for the Gly972Arg IRS-1 variant and on 2-h plasma glucose for the Gly1057Asp IRS-2 variant. The Gly972Arg IRS-1 variant was more prevalent in insulin-resistant patients compared with non–insulin-resistant individuals or control subjects (39.3 vs. 4.0 and 16.6%, P < 0.0031, respectively). A multivariate model that included BMI as a variable revealed significant effects of the Gly1057Asp IRS-2 variant on insulin resistance (P < 0.016, odds ratio [OR] 7.2, 95% CI 1.29–43.3). HOMAIR was higher in carriers of both IRS variants than in those with IRS-2 mutations only or those with wild-type variants (6.2 ± 2.3, 2.8 ± 0.5, and 1.8 ± 0.2, respectively; P < 0.01), and it was significantly associated with this genotype (P < 0.0085, OR 1.7, 95% CI 1.09–2.99). We conclude that polymorphic alleles of both IRS-1 and IRS-2, alone or in combination, may have a functional impact on the insulin-resistant component of PCOS.
Footnotes
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Address correspondence and reprint requests to Florin Grigorescu, IURC, Molecular Endocrinology, 641 Ave. Du Doyen Gaston Giraud, 34093 Montpellier Cedex 5, France. E-mail: florin{at}iurc1.iurc.montp.inserm.fr.
Received for publication 18 August 2000 and accepted in revised form 21 May 2001.
AUC, area under the curve; AUCgluc, AUC for glucose; AUCins, AUC for insulin; FSH, follicle-stimulating hormone; LH, leutenizing hormone; HOMAIR, homeostasis model assessment index for insulin resistance; IGT, impaired glucose tolerance; IR, insulin receptor; IRS, IR substrate; OGTT, oral glucose tolerance test; OR, odds ratio; PCOS, polycystic ovary syndrome; PCR, polymerase chain reaction; UTR, untranslated region.
