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

Mkadem, Samira Ait El; Lautier, Corinne; Macari, Françoise; Molinari, Nicolas; Lefèbvre, Patrick; Renard, Éric; Gris, Jean‐Christophe; Cros, Gérard; Daurès, Jean Pierre; Bringer, J.; White, Morris F.; Grigorescu, Florin

doi:10.2337/diabetes.50.9.2164

Cited by 127 publications

(101 citation statements)

References 24 publications

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“…Allele frequencies were in Hardy-Weinberg equilibrium in each racial/ethnic group. The frequency of the variant allele was 0.06 for nonHispanic whites and 0.07 for African Americans; these frequencies were similar to the value of 0.07 (range 0.051-0.11) previously described for a general population sample [40].…”

Section: Resultssupporting

confidence: 88%

An association between a common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal breast cancer survivors

Fan

McKean‐Cowdin

Bernstein

et al. 2006

Breast Cancer Res Treat

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Insulin receptor substrate-1 (IRS-1) is a key downstream signaling molecule common to both the insulin and IGF signaling pathways that can interact with the estrogen pathway to regulate breast cell growth. We investigated whether a putative functional variant for IRS-1 (G972R) influences circulating levels of sex hormones, sex hormone binding globulin (SHBG), C-peptide, and insulinlike growth factor 1 (IGF-1) levels among postmenopausal African-American and non-Hispanic white breast cancer patients enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study. Circulating levels of sex hormones and growth factors can influence breast cancer recurrence and survival. Serum estrone, estradiol, testosterone, SHBG, IGF-1 and C-peptide were measured in 468 patients at 30+ months post diagnosis. Non-protein bound hormone levels (free estradiol, free testosterone) were calculated. In African-American patients, the IRS-1 variant was associated with increased serum levels of estrone (p=0.02), free estradiol (p=0.04), total testosterone (p=0.04), free testosterone (p=0.006) and decreased levels of sex hormone-binding globulin (p=0.02). No association was present for white patients. Our findings provide suggestive evidence that IRS-1 G972R variant may be associated with circulating levels of sex hormones and SHBG in African American breast cancer survivors.

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Section: Resultssupporting

confidence: 88%

An association between a common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal breast cancer survivors

Fan

McKean‐Cowdin

Bernstein

et al. 2006

Breast Cancer Res Treat

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“…In Caucasians, Finns, and Chinese, however, this variant was not associated with type 2 diabetes (5,6). Although the polymorphism was associated with decreased insulin sensitivity and impaired glucose tolerance in women with polycystic ovary syndrome (7), it showed no association with insulin sensitivity in other studies (6,8,9). In contrast, another study in women with polycystic ovary syndrome found that homozygous carriers of the Gly1057 allele had higher 2-h plasma glucose concentrations during an oral glucose tolerance test (OGTT) (10).…”

mentioning

confidence: 89%

Metabolic Effects of the Gly1057Asp Polymorphism in IRS-2 and Interactions With Obesity

et al. 2003

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Insulin receptor substrate (IRS)-2 plays an important role in insulin signaling and its disruption results in diabetes in mice. In humans, the IRS-2 Gly1057Asp substitution was associated with lower risk of type 2 diabetes in lean individuals, but with a higher risk in obese individuals. To clarify the role of IRS-2 on the development of type 2 diabetes and obesity in Pima Indians, and particularly to investigate whether the effects of the Gly1057Asp polymorphism on metabolism are mediated by obesity, molecular scanning of the gene for mutations was performed and interaction of the polymorphism with obesity was tested. We identified the previously described Gly1057Asp mutation as well as a rare Asp819His mutation and four silent polymorphisms. The effect of the Gly1057Asp mutation on type 2 diabetes and obesity was tested in a large cohort of Pima Indians (n ‫؍‬ 998). A subgroup of nondiabetic full-heritage Pima Indians (n ‫؍‬ 233) had measurements of body composition, glucose tolerance, insulin action (M), endogenous glucose production (EGP; hyperinsulinemic clamp), acute insulin response (AIR, 25-g intravenous glucose tolerance test, n ‫؍‬ 118 normal glucosetolerant subjects), and percutaneous fat biopsy specimens from the periumbilical region (n ‫؍‬ 160). A total of 132 nondiabetic subjects were included in longitudinal analyses. The frequency of the Asp1057 allele was 0.6. In cross-sectional analyses, subjects homozygous for the Asp1057 allele (Asp/Asp) had a higher prevalence of type 2 diabetes than heterozygote individuals and subjects homozygous for the Gly1057 allele (X/Gly, P ‫؍‬ 0.04). There was no effect on BMI (P ‫؍‬ 0.78) or gene-BMI interaction on the prevalence of type 2 diabetes (P ‫؍‬ 0.57). In the nondiabetic subgroup, subjects with Asp/Asp had higher percent body fat (P ‫؍‬ 0.01), BMI (P ‫؍‬ 0.02), and waist circumference (P ‫؍‬ 0.004), but there was no difference in metabolic characteristics (all P > 0.2). However, the relationship between percent body fat and fasting glucose, basal EGP, EGP during the clamp, AIR, and subcutaneous abdominal adipocyte size was significantly different in the Asp/Asp group (P for interaction ‫؍‬ 0.02, 0.06, 0.0007, 0.08, and 0.006, respectively) compared with the X/Gly group, suggesting a more detrimental effect of Asp homozygosity on these traits with increasing percent body fat. In longitudinal analyses, among subjects in the upper tertile of change in percent body fat, those with Asp/Asp had a larger increase in fasting and postprandial glycemia and basal EGP and a larger decrease in M and AIR than subjects with X/Gly, independent of change in obesity (all P < 0.05). In conclusion, our findings suggest that the association of homozygosity for the Asp1057 allele in IRS-2 with type 2 diabetes in Pima Indians may be mediated by interaction of the polymorphism with obesity on several diabetes-related traits. Diabetes 52:1544 -1550, 2003 I nsulin receptor substrate (IRS)-2 plays an important role in insulin signaling. Together with IRS-1, it mediates most insulin ...

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“…In Caucasians, Finns, and Chinese, however, this variant has not shown an associated with type 2 diabetes [58,59]. Although the polymorphism was associated with decreased insulin sensitivity and impaired glucose tolerance in women with polycystic ovary syndrome [60], it showed no association with insulin sensitivity in other studies [59,61,62]. In contrast, another study in women with polycystic ovary syndrome found that homozygous carriers of the Gly1057 allele had higher 2-h plasma glucose concentrations during an oral glucose tolerance test (OGTT) [63].…”

Section: Mutations Of Irs As a Cause Of Insulin Resistancementioning

confidence: 92%

The Metabolic Syndrome in Hispanics – The Role of Insulin Resistance and Inflammation

Arora¹

2012

Insulin Resistance

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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

Cited by 127 publications

References 24 publications

An association between a common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal breast cancer survivors

An association between a common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal breast cancer survivors

Metabolic Effects of the Gly1057Asp Polymorphism in IRS-2 and Interactions With Obesity

The Metabolic Syndrome in Hispanics – The Role of Insulin Resistance and Inflammation

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