Genetic Determinants of Insulin Action in Polycystic Ovary Syndrome

Haap, Michael; Machicao, Fausto; Stefan, Norbert; Thamer, Claus; Tschritter, Otto; Schnuck, F.; Wallwiener, D.; Stümvoll, Michael; Häring, H.-U.; Fritsche, Andreas

doi:10.1055/s-2005-837665

Cited by 66 publications

(53 citation statements)

References 27 publications

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“…Whereas most studies (9)(10)(11)(12)14,15), present study included, reported no association between Pro12Ala genotype and PCOS diagnosis, a few reported that the Pro12Ala G allele was significantly less frequent in PCOS versus control women (13,16). Additionally, some studies reported significant increases in insulin sensitivity (decreased HOMA-IR) and decreases in fasting insulin and glucose levels (8-10) and lower hirsutism score (9) in PCOS women with the Pro12Ala G allele; whereas others (7,11,14), including this study, reported no association with fasting glucose and insulin or changes in HOMA-IR in those with PCOS. Only a subset of the subjects in our study was phenotyped for insulin-related traits, which may explain why we did not observe association with these traits in subjects with PCOS; however, this subset was still greater in number than each of the reports that did find an effect of Pro12Ala on insulin-related traits.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a polymorphism in exon 2 of the PPARγ2 isoform, resulting in a Pro12Ala substitution, influences the risk of type 2 diabetes with the rarer Ala allele associated with a lower incidence of diabetes (6). Several small studies have looked at the effects of the Pro12Ala and a silent exon 6 polymorphism (His447His) in association with PCOS, though they have produced conflicting results (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). To better understand the role of these polymorphisms in PCOS, we examined the Pro12Ala and silent exon 6 polymorphism in a cohort of 285 women with PCOS and 187 controls, the largest sample size of all published reports of PPARG in PCOS to date.…”

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confidence: 99%

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Genetic variants in peroxisome proliferator-activated receptor gamma influence insulin resistance and testosterone levels in normal women, but not those with polycystic ovary syndrome

Antoine

Pall

Trader

et al. 2007

Fertility and Sterility

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Polymorphisms in PPARG implicated in previous studies of metabolic traits do not appear to influence component phenotypes of PCOS, but do affect androgens and insulin resistance in the general population.Objective-To investigate the relationship of the PPARG Pro12Ala and silent exon 6 (His447His) polymorphisms with the clinical features of polycystic ovary syndrome (PCOS).Design-PCOS and control subjects were genotyped for Pro12Ala and His447His; associations between genotype, diagnosis, and hormonal/metabolic parameters were assessed.Setting-Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; control subjects were recruited from the surrounding community. Genotyping was performed at Cedars-Sinai Medical Center in Los Angeles.Reprint Request: Mark O. Goodarzi, M.D., Ph.D., Cedars-Sinai Medical Center, Division of Endocrinology, Diabetes and Metabolism, 8700 Beverly Blvd., Los Angeles, CA 90048, email: mark.goodarzi@cshs.org Presented in part at the 87 th Annual Meeting of the Endocrine Society, San Diego, June 4-7, 2005 Supported by:This study was supported in part by the Helping Hand of Los Angeles, and by grants R01-HD29364 and K24-HD01346 from the National Institutes of Health (to RA). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Result(s)-Pro12Ala and His447His did not influence risk of PCOS or its component phenotypes in PCOS patients. In controls, Pro12Ala did not influence measures of insulin resistance or androgen production; however, carriers of the His447His T allele had significantly decreased free and total testosterone levels and HOMA-IR. Furthermore, haplotypes in controls bearing the His447His T allele were also associated with decreased testosterone. Conflict of Interest NIH Public AccessConclusion(s)-does not appear to be an important modifier gene in PCOS. In controls, however, the His447His T allele may be in linkage disequilibrium with a functional variant that influences insulin resistance and testosterone production. Keywordsperoxisome proliferator activated receptor gamma; polycystic ovary syndrome; single nucleotide polymorphism; testosterone; insulin resistance Polycystic ovary syndrome (PCOS) is a common disorder affecting 6-8% of reproductive aged women (1) and clinically manifests as menstrual irregularities, hyperandrogenism, polycystic ovaries, and often obesity. Several studies demonstrate substantial familial aggregation of PCOS with most showing significantly higher rates of PCOS among first-degree relatives when compared to the general population (2,3). Fifty to s...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Genetic variants in peroxisome proliferator-activated receptor gamma influence insulin resistance and testosterone levels in normal women, but not those with polycystic ovary syndrome

Antoine

Pall

Trader

et al. 2007

Fertility and Sterility

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“…After review, a total of 16 published articles reported on the relationship between these two IRS gene polymorphisms and PCOS met the inclusion criteria [12][13][14][15][19][20][21][22][23][24][25][26][27][28][29], 15/16 were about the Gly972Arg polymorphism, 5/16 were about the Gly1057Asp polymorphism. These articles were published between 2001 and 2011.…”

Section: Eligibility Of Studiesmentioning

confidence: 99%

Association of IRS-1 and IRS-2 genes polymorphisms with polycystic ovary syndrome: a meta-analysis

Ruan

Xie

2012

Endocr J

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POLYCYSTIC OvarY SYndrOme (PCOS)is one of the most common heterogeneous endocrine disorders, which affect 5%-10% of women in reproductive age and is a leading causes of female infertility [1]. It is characterized by menstrual irregularity, hyperandrogenism, insulin resistance, and increased risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) [2,3]. Candidate genes for etiology of PCOS involve in ovarian and adrenal steroidogenesis, steroid hormone actions, gonadotropin action and regulation, insulin action and secretion, energy homeostasis, chronic inflammation and others [4]. Yet the "PCOS genes" remain elusive. Insulin resistance is a key component in the pathogenesis of PCOS and the predisposition to type 2 diabetes [5,6], however, the mechanisms for defects in insulin signaling in the disorder are comAssociation of IRS-1 and IRS-2 genes polymorphisms with polycystic ovary syndrome: a meta-analysis Yuan Ruan, Jianhua Ma and Xiaojing Xie Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China abstract. Insulin resistance (IR) plays an important role in the pathogenesis of polycystic ovary syndrome (PCOS) which is a common disorder in premenopausal women. The association between the single nucleotide polymorphisms (SNPs) of insulin receptor substrate (IRS) gene and PCOS in several populations has been studied, but the results are conflicting. The aim of this study was undertaken to investigate association of IRS-1 and IRS-2 genes polymorphisms with PCOS by conducting a meta-analysis. Literature search was conducted through PubMed and EMBASE databases (up to July 31, 2011). Fifteen articles with 1,358 cases and 1,561 controls were enrolled in the meta-analysis of the association between Gly972Arg variant and PCOS, and five articles with 519 cases and 883 controls were enrolled in the meta-analysis of Gly1057Asp variant. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed and random-effects models. The Q-statistic test was used to assess heterogeneity, and Begg's test and Egger's test were used to evaluate publication bias. Sensitivity analysis was also performed. Our results indicated that A allele of Gly972Arg conferred a significantly increased risk of PCOS compared with G allele (OR = 1.91, 95% CI: 1.36-2.68). However, in Gly1057Asp polymorphism the OR of allele A vs. G is 0.92 (95% CI: 0.72, 1.18). Our meta-analysis suggested that IRS-1 Gly972Arg polymorphism might be considered a significant risk for PCOS. Otherwise, no significant associations were observed in IRS-2 Gly1057Asp polymorphism which needs to be further confirmed by further studies.Key words: Insulin receptor substrate, Polymorphisms, Polycystic ovary syndrome, Meta-analysis plex and have not been fully elucidated [7,8].Insulin receptor substrates proteins (IRS) are critical for insulin mediated signal transduction in insulin target tissues. Several studies have shown that two common polymorphisms in IRS particularly Gly972Arg (rs1801278) in ...

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“…51 A second single nucleotide polymorphism, T45G, has been investigated in relation to PCOS, and studies have shown a statistically definable Adipokines in reproduction DB Campos et al correlation between the occurrence of this gene form and the ovarian disorder. 52,53 Recent findings indicate that adiponectin may also be active in the uterus and placenta. Both AdipoR1 and R2 are highly expressed in the endometrium of the pig.…”

Section: Effects Of Adiponectin On Reproduction and Fertilitymentioning

confidence: 99%

The ‘beneficial’ adipokines in reproduction and fertility

et al. 2007

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The objective of this study was to review the available information on the signaling proteins produced by adipose tissue in the context of their role in regulating reproductive processes, including ovarian and uterine function. It is well known that both obesity and excessive leanness are associated with reproductive dysfunction. Adipokines are cytokines predominately or exclusively expressed by adipose tissue that circulate and affect target tissues. Four known adipokines, adiponectin, visfatin/ PBEF, omentin and vaspin, all increase tissue sensitivity to insulin, and are thus described as 'beneficial'. There is strong support for a role for adiponectin in the function of the ovary and placenta. There is evidence for direct effects of this adipokine on the late stages of folliculogenesis, and additive interactions of adiponectin with insulin and gonadotropins in inducing periovulatory changes in ovarian follicles. In addition, clinical and genomic studies associate hypoadiponectinemia with obesity-related reproductive disorders, including the polycystic ovarian syndrome. The roles for visfatin/PBEF, omentin and vaspin in reproduction remain to be established. The conclusion thus drawn is that the expression of insulin-sensitizing adipokines varies with adipose abundance. These adipokines have demonstrated both the potential effects on ovarian function and the possible effects on the formation of the placenta, acting through multiple mechanisms.

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Genetic Determinants of Insulin Action in Polycystic Ovary Syndrome

Cited by 66 publications

References 27 publications

Genetic variants in peroxisome proliferator-activated receptor gamma influence insulin resistance and testosterone levels in normal women, but not those with polycystic ovary syndrome

Genetic variants in peroxisome proliferator-activated receptor gamma influence insulin resistance and testosterone levels in normal women, but not those with polycystic ovary syndrome

Association of IRS-1 and IRS-2 genes polymorphisms with polycystic ovary syndrome: a meta-analysis

The ‘beneficial’ adipokines in reproduction and fertility

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