Insulin Resistance in Polycystic Ovary Syndrome: Progress and Paradoxes

Venkatesan, Aranapakam M.

doi:10.1210/rp.56.1.295

Cited by 135 publications

(90 citation statements)

References 46 publications

(64 reference statements)

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“…AIT is supposed to be related to variants in the HLA and CTLA-4 genes. In contrast, PCOS is related to genetic predispositions for insulin resistance (40), especially defects in insulin signaling pathways (41), genetic variants in LH (42), follistatin and to CYP11a, a gene coding for P450 cholesterol side chain cleavage (43). To date, a common genetic background has not been found.…”

Section: Discussionmentioning

confidence: 99%

High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome

Janßen

Mehlmauer

Hahn

et al. 2004

European Journal of Endocrinology

271

190

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Objective: To investigate the prevalence of autoimmune thyroiditis (AIT) in patients with polycystic ovary syndrome (PCOS). Design: Over a period of 30 months, 175 patients with PCOS were recruited to a prospective multicenter study to evaluate thyroid function and morphology; 168 age-matched women without PCOS were studied as a control group. Methods: PCOS was defined as a-or oligomenorrhea, hyperandrogenism and exclusion of other disturbances of estrogen or androgen synthesis. All laboratory parameters were determined with automated immunoassays. Thyroid morphology was assessed by ultrasound. Results: PCOS patients were characterized by an increased LH/FSH ratio, low progesterone, elevated testosterone and a high prevalence of hirsutism (PCOS 83%, control 3%; mean hirsutism score 12^5 and 3^2 respectively), but no differences in estrogen levels were found. Thyroid function and thyroidspecific antibody tests revealed elevated thyroperoxidase (TPO) or thyroglobulin (TG) antibodies in 14 of 168 controls (8.3%), and in 47 of 175 patients with PCOS (26.9%; P , 0.001). On thyroid ultrasound, 42.3% of PCOS patients, but only 6.5% of the controls (P , 0.001) had a hypoechoic tissue typical of AIT; while thyroid hormone levels were normal in all subjects, PCOS patients had a higher mean TSH level (P , 0.001) and a higher incidence of TSH levels above the upper limit of normal (PCOS 10.9%, controls 1.8%; P , 0.001). Conclusion: This prospective study demonstrates a threefold higher prevalence of AIT in patients with PCOS, correlated in part with an increased estrogen-to-progesterone ratio and characterized by early manifestation of the disease.

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Section: Discussionmentioning

confidence: 99%

High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome

Janßen

Mehlmauer

Hahn

et al. 2004

European Journal of Endocrinology

271

190

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“…10 As a compensatory response to insulin resistance, hyperinsulinaemia develops which in turn interacts synergistically with luteinising hormone (LH) as a co-gonadotrophin within ovarian theca cells. 11 Resultant activation of CYP17 (encoding P450c17α, a key enzyme in ovarian androgen biosynthesis) in turn enhances the generation and release of androgens.…”

Section: Insulin Resistance In the Pathogenesis Of Pcosmentioning

confidence: 99%

Polycystic ovary syndrome: insight into pathogenesis and a common association with insulin resistance

et al. 2016

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Polycystic ovary syndrome (PCOS) is a common condition that typically develops in reproductive-age women. The cardinal clinical and biochemical characteristics of PCOS include reproductive dysfunction and hyperandrogenic features. PCOS is also strongly associated with obesity based on data from epidemiological and genetic studies. Accordingly, PCOS often becomes manifest in those women who carry a genetic predisposition to its development, and who also gain weight. The role of weight gain and obesity in the development of PCOS is mediated at least in part, through worsening of insulin resistance. Compensatory hyperinsulinaemia that develops in this context disrupts ovarian function, with enhanced androgen production and arrest of ovarian follicular development. Insulin resistance also contributes to the strong association of PCOS with adverse metabolic risk, including dysglycaemia, dyslipidaemia and fatty liver. Conversely, modest weight loss of just 5% body weight with improvement in insulin sensitivity, frequently results in clinically meaningful improvements in hyperandrogenic, reproductive and metabolic features. Future developments of novel therapies for obese women with PCOS should focus on promotion of weight loss and improvement in insulin sensitivity. In this context, therapies that complement lifestyle changes such as dietary modification and exercise, particularly during the maintenance phase of weight loss are important. Putative novel targets for therapy in PCOS include human brown adipose tissue

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“…Serine phosphorylation of the IR, IGF-1R, and IRS-1 has been proposed to be a negative regulatory mechanism (21,58) and cause insulin resistance. Tumor necrosis factor can stimulate phosphorylation of serine 307 in IRS-1 (59) and insulin resistance.…”

Section: Igf-1r Kinase Activity Is Enhanced In Mcf-7 Cellsmentioning

confidence: 99%

RACK1 Is an Insulin-like Growth Factor 1 (IGF-1) Receptor-interacting Protein That Can Regulate IGF-1-mediated Akt Activation and Protection from Cell Death

Kiely¹,

Sant²,

O’Connor³

2002

Journal of Biological Chemistry

140

133

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The insulin receptor and insulin-like growth factor 1 receptor (IGF-1R), activated by their ligands, control metabolism, cell survival, and proliferation. Although the signaling pathways activated by these receptors are well characterized, regulation of their activity is poorly understood. To identify regulatory proteins we undertook a two-hybrid screen using the IGF-1R ␤-chain as bait. This screen identified Receptor for Activated C Kinases (RACK1) as an IGF-1R-interacting protein. RACK1 also interacted with the IGF-1R in fibroblasts and MCF-7 cells and with endogenous insulin receptor in COS cells. Interaction with the IGF-1R did not require tyrosine kinase activity or receptor autophosphorylation but did require serine 1248 in the C terminus. Overexpression of RACK1 in either R؉ fibroblasts or MCF-7 cells inhibited IGF-1-induced phosphorylation of Akt, whereas it enhanced phosphorylation of Erks and Jnks. Src, the p85 subunit of phosphatidylinositol 3-kinase, and SHP-2 were all associated with RACK1 in these cells. Interestingly, the proliferation of MCF-7 cells was enhanced by overexpression of RACK1, whereas IGF-1-mediated protection from etoposide killing was greatly reduced. Altogether the data indicate that RACK1 is an IGF-1R-interacting protein that can modulate receptor signaling and suggest that RACK1 has a particular role in regulating Akt activation and cell survival.The insulin and IGF-1 1 receptors (IR and IGF-1R) belong to a family of tyrosine kinase receptors that also includes the insulin-related receptor. They are tetrameric receptors made up of two ␣-subunits that bind the ligands insulin, IGF-1 or IGF-2, and two ␤-subunits that share high homology in their kinase domains (reviewed in Ref. 1). These receptors are homologous to a receptor found in the nematode Caenorhabditis elegans and in Drosophila, and they activate an evolutionarily conserved metabolic and survival signaling pathway that includes insulin-related substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3-K), the serine/threonine kinase Akt, and the Forkhead family of transcription factors (2-5).

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Insulin Resistance in Polycystic Ovary Syndrome: Progress and Paradoxes

Cited by 135 publications

References 46 publications

High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome

High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome

Polycystic ovary syndrome: insight into pathogenesis and a common association with insulin resistance

RACK1 Is an Insulin-like Growth Factor 1 (IGF-1) Receptor-interacting Protein That Can Regulate IGF-1-mediated Akt Activation and Protection from Cell Death

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