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.
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 [HOMA(IR)] 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). HOMA(IR) 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.
El Mkadem
S A
SA
Molecular Endocrinology Laboratory, Institut Universitaire de Recherche Cilnique, Montpellier, France.
Lautier
C
C
Macari
F
F
Molinari
N
N
Lefèbvre
P
P
Renard
E
E
Gris
J C
JC
Cros
G
G
Daurès
J P
JP
Bringer
J
J
White
M F
MF
Grigorescu
F
F
D000328:Adult; D000483:Alleles; D005260:Female; D018628:Gene Dosage; D014644:Genetic Variation; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics*; D011085:Polycystic Ovary Syndrome / Q000235:genetics* / Q000503:physiopathology*; D012016:Reference Values
C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins