Assessing and treating insulin resistance in women with polycystic ovarian syndrome

Polycystic ovarian syndrome(PCOS) is a highly prevalent hormonal and metabolic disorder among reproductive aged women worldwide.Women with PCOS have widely varying phenotypes and seek medical care for differing reasons.In addition to concern for menstrual cycle function,ovulation,hirsutism and acne,many PCOS women have abnormal glucose metabolism.While diabetes mellitus and impaired glucose tolerance are easily diagnosed,the diagnosis of and concern for insulin resistance as a precursor disorder is underappreciated.Insulin resistance may be the first important marker of metabolic disease in PCOS women at risk for metabolic syndrome and coronary artery disease.     

Reproductive tissues maintain insulin sensitivity in diet-induced obesity

Reproductive dysfunction is associated with obesity. We previously showed that female mice with diet-induced obesity (DIO) exhibit infertility and thus serve as a model of human polycystic ovary syndrome (PCOS). We postulated that differential insulin signaling of tissues leads to reproductive dysfunction; therefore, a comparison of insulin signaling in reproductive tissues and energy storage tissues was performed. Pituitary-specific insulin receptor knockout mice were used as controls. High-fat diet-induced stress, which leads to insulin resistance, was also investigated by assaying macrophage infiltration and phosphorylated Jun NH(2)-terminal kinase (pJNK) signaling. In lean mice, reproductive tissues exhibited reduced sensitivity to insulin compared with peripheral metabolic tissues. However, in obese mice, where metabolic tissues exhibited insulin resistance, the pituitary and ovary maintained insulin sensitivity. Pituitaries responded to insulin through insulin receptor substrate (IRS)2 but not IRS1, whereas in the ovary, both IRS1 and IRS2 were activated by insulin. Macrophage infiltration and pJNK signaling were not increased in the pituitary or ovary of lean mice relative to DIO mice. The lack of inflammation and cytokine signaling in the pituitary and ovary in DIO mice compared with lean mice may be one of the reasons that these tissues remained insulin sensitive. Retained sensitivity of the pituitary and ovary to insulin may contribute to the pathophysiology of PCOS.     

多囊卵巢综合征与复发性流产的研究进展

复发性流产(RSA)的发生与多种因素相关,包括年龄、遗传、内分泌与代谢障碍、免疫因素、子宫发育异常、血栓形成倾向、感染、精液质量和生活方式等。多囊卵巢综合征(PCOS)是一种以持续性无排卵、多卵泡不成熟、雄激素水平升高和胰岛素抵抗为主要特征的生殖功能障碍与糖代谢异常并存的内分泌紊乱综合征。PCOS患者RSA的发生率明显高于普通人群,30%~40%的PCOS患者存在自然流产史。目前,PCOS患者易发生RSA的具体发病机制尚不明确,可能与高黄体生成素血症、高雄激素血症、胰岛素抵抗、肥胖、高泌乳素血症、黄体功能不全、血栓形成等有关。本文从上述方面对PCOS患者发生RSA的常见原因及其预防进行综述。     

腹型肥胖与多囊卵巢综合征

腹型肥胖、超重和肥胖是多囊卵巢综合征（PCOS）的常见症状。腹型肥胖和胰岛素抵抗可能引起卵巢和肾上腺分泌过多的雄激素,而雄激素过多分泌本身就可引起脂肪向腹部沉积。PCOS患者内脏脂肪的最新基因组学和蛋白组学研究发现其基因表达和蛋白质组成存在异常。本文综述了有关雄激素过多引起腹壁脂肪沉积,进一步促进PCOS患者卵巢和肾上腺雄激素的过多分泌的机制。     

Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome

Insulin resistance in skeletal muscle is a major risk factor for the development of type 2 diabetes in women with polycystic ovary syndrome (PCOS). In patients with type 2 diabetes, insulin resistance in skeletal muscle is associated with abnormalities in insulin signaling, fatty acid metabolism, and mitochondrial oxidative phosphorylation (OXPHOS). In PCOS patients, the molecular mechanisms of insulin resistance are, however, less well characterized. To identify biological pathways of importance for the pathogenesis of insulin resistance in PCOS, we compared gene expression in skeletal muscle of metabolically characterized PCOS patients (n = 16) and healthy control subjects (n = 13) using two different approaches for global pathway analysis: gene set enrichment analysis (GSEA 1.0) and gene map annotator and pathway profiler (GenMAPP 2.0). We demonstrate that impaired insulin-stimulated total, oxidative and nonoxidative glucose disposal in PCOS patients are associated with a consistent downregulation of OXPHOS gene expression using GSEA and GenMAPP analysis. Quantitative real-time PCR analysis validated these findings and showed that reduced levels of peroxisome proliferator-activated receptor gamma coactivator alpha (PGC-1alpha) could play a role in the downregulation of OXPHOS genes in PCOS. In these women with PCOS, the decrease in OXPHOS gene expression in skeletal muscle cannot be ascribed to obesity and diabetes. This supports the hypothesis of an early association between insulin resistance and impaired mitochondrial oxidative metabolism, which is, in part, mediated by reduced PGC-1alpha levels. These abnormalities may contribute to the increased risk of type 2 diabetes observed in women with PCOS.     

Markers of insulin resistance in Polycystic ovary syndrome women: An update

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders, affecting 5%-10% of women of reproductive age. The importance of this syndrome lies in the magnitude of associated comorbidities: infertility, metabolic dysfunction, cardiovascular disease (CVD), plus psychological and oncological complications. Insulin resistance (IR) is a prominent feature of PCOS with a prevalence of 35%-80%. Without adequate management, IR with compensatory hyperinsulinemia contributes directly to reproductive dysfunction in women with PCOS. Furthermore, epidemiological data shows compelling evidence that PCOS is associated with an increased risk of impaired glucose tolerance, gestational diabetes mellitus and type 2 diabetes. In addition, metabolic dysfunction leads to a risk for CVD that increases with aging in women with PCOS. Indeed, the severity of IR in women with PCOS is associated with the amount of abdominal obesity, even in lean women with PCOS. Given these drastic implications, it is important to diagnose and treat insulin resistance as early as possible. Many markers have been proposed. However, quantitative assessment of IR in clinical practice remains a major challenge. The gold standard method for assessing insulin sensitivity is the hyperinsulinemic euglycemic glucose clamp. However, it is not used routinely because of the complexity of its procedure. Consequently, there has been an urgent need for surrogate markers of IR that are more applicable in large population-based epidemiological investigations. Despite this, many of them are either difficult to apply in routine clinical practice or useless for women with PCOS. Considering this difficulty, there is still a need for an accurate marker for easy, early detection and assessment of IR in women with PCOS. This review highlights markers of IR already used in women with PCOS, including new markers recently reported in literature, and it establishes a new classification for these markers.     

Polymorphism of insulin gene variable number tandem repeats correlated with polycystic ovary syndrome

Objective: To investigate the correlation between the insulin gene variable number tandem repeats (INS-VN-TR) with polycystic ovary syndrome(PCOS) and metabolic features related to insulin resistance (IR).Methods: One hundred and thirty patients with PCOS (PCOS group) and 130 normal women (control group) were included. Genotyping of INS-VNTR was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).Results: The distribution of genotype of INS-VNTR was similar in PCOS group, but the Ⅲ allele frequency of INS-VNTR was higher in PCOS patients than that in controls, and Logistic regression analysis revealed that the Ⅲ allele was associated with increased risk of PCOS[adjusted odd ratio(OR) = 2.31;95% confidence interval(CD =1.07-4.98), compared with the Ⅰ allele. The distribution of genotype and the Ⅲ allele frequency of INS-VNTR in PCOS insulin resistance (PCOS-IR) group were significantly higher than that in PCOS non-insulin resistance group (PCOS-NIR). Moreover, PCOS women with Ⅲ allele had statistically significantly higher fasting insulin level and HOMA-IR than those of PCOS women with Ⅰ allele.Conclusion: INS-VNTR may not be a susceptibility gene, but INS-VNTR polymorphism may play an important role in the occurrence of insulin resistance in patients with PCOS.     

Fuel selection in human skeletal muscle in insulin resistance: a reexamination

For many years, the Randle glucose fatty acid cycle has been invoked to explain insulin resistance in skeletal muscle of patients with type 2 diabetes or obesity. Increased fat oxidation was hypothesized to reduce glucose metabolism. The results of a number of investigations have shown that artificially increasing fat oxidation by provision of excess lipid does decrease glucose oxidation in the whole body. However, results obtained with rodent or human systems that more directly examined muscle fuel selection have found that skeletal muscle in insulin resistance is accompanied by increased, rather than decreased, muscle glucose oxidation under basal conditions and decreased glucose oxidation under insulin-stimulated circumstances, producing a state of "metabolic inflexibility." Such a situation could contribute to the accumulation of triglyceride within the myocyte, as has been observed in insulin resistance. Recent knowledge of insulin receptor signaling indicates that the accumulation of lipid products in muscle can interfere with insulin signaling and produce insulin resistance. Therefore, although the Randle cycle is a valid physiological principle, it may not explain insulin resistance in skeletal muscle.     

Leptin impairs insulin signaling in rat adipocytes

Leptin modulates glucose homeostasis by acting as an insulin-sensitizing factor in most insulin target tissues. Nevertheless, insulin-dependent glucose uptake in white adipose tissue decreases after in vivo treatment with leptin. Moreover, elevated leptin concentrations inhibit insulin metabolic effects in adipocytes. Here we studied both, direct and centrally mediated effects of leptin on insulin signaling in rat adipocytes. Adipocyte incubation with low leptin concentrations did not modify the insulin stimulation of mitogen-activated protein kinase (MAPK). However, at elevated concentrations, leptin impaired insulin-stimulated MAPK activity, glycogen synthase kinase (GSK)3beta phosphorylation, and insulin receptor tyrosine phosphorylation without altering vanadate stimulation. An increase of suppressor of cytokine signaling-3 protein was also observed. Central administration of leptin decreased insulin effects on adipocyte MAPK and GSK3beta phosphorylation. In insulin-resistant aged rats with hyperleptinemia and central leptin resistance, insulin poorly stimulated MAPK and central leptin infusion did not further deteriorate adipocyte insulin responsiveness. Food restriction increased MAPK stimulation by insulin and restored the ability of centrally infused leptin to attenuate adipocyte insulin signaling in aged rats. We conclude that leptin can modulate, in an inhibitory manner, adipocyte insulin signaling by two different ways: as an autocrine signal and, indirectly, through neuroendocrine pathways. These mechanisms may be of relevance in situations of hyperleptinemia, such as aging and/or obesity.     

多囊卵巢综合征青年患者血清脂联素、胰岛素抵抗关系的研究

目的探讨多囊卵巢综合征（PCOS）青年患者血清脂联素（APN）、抵抗素（RST）水平与胰岛素抵抗（1R）的关系。方法PCOS组为38例青年PCOS患者,对照组为27例健康女性,两组中根据体重指数（BMI）分为肥胖组BMI（≥25kg／m^2）和非肥胖组（BMI〈25kg／m^2）。在月经第3～5天晨（PCOS闭经者B超检查无优势卵泡当天）留空腹血。采用酶联免疫吸附法（ELISA）测定血清APN和RST浓度,葡萄糖氧化酶法测定血糖浓度,化学发光法测定胰岛素浓度,根据后两者计算胰岛素敏感指数（ISI）。结果（1）肥胖组与非肥胖组空腹血糖水平比较,差异无统计学意义（P〉0．05）;（2）肥胖组与非肥胖组中,PCOS组的空腹胰岛素水平分别显著高于对照组（P〈0．05）;（3）肥胖组中,PCOS组血清APN和ISI水平显著低于对照组,血清RST水平显著高于对照组（P〈0．05）;（4）非肥胖组中,PCOS组血清APN和ISI水平显著低于对照组,血清RST水平显著高于对照组（P〈0．05）。结论（1）与对照组相比,青年PCOS患者血清中APN水平较低,RST水平较高,其中PCOS肥胖患者尤为明显。（2）青年PCOS患者血清中APN水平的下降和RST水平的升高可能与胰岛素敏感性及IR相关。     

胰岛素抵抗与多囊卵巢综合征

多囊卵巢综合征(PCOS)是妇科常见的内分泌疾病,其发病机理可能涉及下丘脑、垂体、肾上腺、胰岛素抵抗、肥胖等多种因素。国外对胰岛素抵抗的研究较多,现就胰岛素抵抗与PCOS进行综述。     

Defect of insulin signal in peripheral tissues: important role of ceramide

In healthy people,balance between glucose production and its utilization is precisely controlled.When circulating glucose reaches a critical threshold level,pancreaticβcells secrete insulin that has two major actions:to lower circulating glucose levels by facilitating its uptake mainly into skeletal muscle while inhibiting its production by the liver.Interestingly,dietary triglycerides are the main source of fatty acids to fulfill energy needs of oxidative tissues.Normally,the unconsumed fraction of excess of fatty acids is stored in lipid droplets that are localized in adipocytes to provide energy during fasting periods.Thus,adipose tissue acts as a trap for fatty acid excess liberated from plasma triglycerides.When the buffering action of adipose tissue to store fatty acids is impaired,fatty acids that build up in othertissues are metabolized as sphingolipid derivatives such as ceramides.Several studies suggest that ceramides are among the most active lipid second messengers to inhibit the insulin signaling pathway and this review describes the major role played by ceramide accumulation in the development of insulin resistance of peripherals tissues through the targeting of specific proteins of the insulin signaling pathway.     

罗格列酮治疗多囊卵巢综合征对改善内分泌、代谢及排卵功能的疗效

目的　探讨罗格列酮 (Rosiglitazone)对多囊卵巢综合征 (PCOS)合并胰岛素抵抗患者内分泌、代谢及排卵功能的影响。　方法　 2 5例PCOS合并胰岛素抵抗患者于自然月经或撤退性出血第 5天服用罗格列酮 12周 ,观察治疗前后血清生殖激素、胰岛素、血糖、血脂水平及排卵功能的变化。　结果　治疗后 ,患者各时相胰岛素 (INS)水平显著下降 (P <0 .0 1)。高密度脂蛋白胆固醇 (HDL C)显著升高 (P <0 .0 1) ,低密度脂蛋白胆固醇 (LDL C)显著降低 (P <0 .0 5 )。患者血清黄体生成素(LH)、黄体生成素 /促卵泡生成素比值 (LH/FSH)、睾酮 (T)和雄烯二酮 (A)水平均显著下降 (P <0 .0 1) ;性激素结合蛋白 (SHBG)水平显著升高 (P <0 .0 1) ;治疗后克罗米酚促排卵成功率为 72 % ,明显高于治疗前 2 0 % (P <0 .0 1)。　结论　罗格列酮通过改善胰岛素抵抗 ,降低胰岛素水平 ,使PCOS患者异常的血激素、血脂及排卵功能得到明显改善。     

Role of oxidative stress in endothelial insulin resistance

The International Diabetes Federation estimates that 316million people are currently affected by impaired glucose tolerance（IGT）.Most importantly,recent forecasts anticipate a dramatic IGT increase with more that 470million people affected by the year 2035.Impaired insulin sensitivity is major feature of obesity and diabetes and is strongly linked with adverse cardiometabolic phenotypes.However,the etiologic pathway linking impaired glucose tolerance and cardiovascular disease remains to be deciphered.Although insulin resistance has been attributed to inflammatory programs starting in adipose tissue,emerging evidence indicates that endothelial dysfunction may represent the upstream event preceding peripheral impairment of insulin sensitivity.Indeed,suppression of reactive oxygen species-dependent pathways in the endothelium has shown to restore insulin delivery to peripheral organs by preserving nitric oxide（NO）availability.Here we describe emerging theories concerning endothelial insulin resistance,with particular emphasis on the role oxidative stress.Complex molecular circuits including endothelial nitric oxide synthase,prostacyclin synthase,mitochondrial adaptor p66^Shc,nicotinamide adenine dinucleotide phosphate-oxidase oxidase and nuclear factor kappa-B are discussed.Moreover,the review provides insights on the effectiveness of available compounds（i.e.,ruboxistaurin,sildenafil,endothelin receptor antagonists,NO donors）in restoring endothelial insulin signalling.Taken together,these aspects may significantly contribute to design novel therapeutic approaches to restore glucose homeostasis in patients with obesity and diabetes.     

Bone Health in Women With Polycystic Ovary Syndrome: A Narrative Review

Bone as an active connective and endocrine tissue is influenced by hormones, physical activity, inflammatory factors, minerals, dietary components, and body weight. Bone fractures are a major cause of decreased quality of life and mortality in humans. Polycystic ovary syndrome (PCOS), is one of the most common endocrine disorders in women of reproductive age worldwide. PCOS is associated with disturbances in androgen and estrogen levels, insulin resistance (IR), obesity, as well as low-grade chronic inflammation, and gut microbiota (GM) dysbiosis, all of which may negatively or positively affect bone metabolism. However, it has not yet been well clarified whether PCOS is bone-protective or bone-destructive. This study aimed to review the association between bone health and PCOS, and summarize its related factors. PubMed, Scopus, and Web of Science databases were searched to retrieve relevant English publications investigating the relationship between bone health and PCOS. Several disorders associated with PCOS can negatively or positively affect bone metabolism. Despite some positive effects of insulin, androgens, estrogens, and obesity on bone, IR, estrogen deficiency, low-grade chronic inflammation, and GM dysbiosis may adversely affect the bone metabolism in PCOS women. Studies comparing bone mineral density or bone metabolism and the risk of bone fractures in women with PCOS have controversial results. Further studies are required to understand the mechanisms underlying bone metabolism in PCOS subjects. Moreover, prospective studies are needed to estimate the risk of bone fractures and osteoporosis in PCOS subjects.     

Obesity-Induced Infertility and Hyperandrogenism Are Corrected by Deletion of the Insulin Receptor in the Ovarian Theca Cell

Women with polycystic ovary syndrome (PCOS) exhibit elevated androgen levels, oligoanovulation, infertility, and insulin resistance in metabolic tissues. The aims of these studies were to determine the role of insulin signaling in the development and function of ovarian theca cells and the pathophysiologic effects of hyperinsulinism on ovarian function in obesity. We disrupted the insulin receptor (IR) gene specifically in the theca-interstitial (TI) cells of the ovaries (Cyp17IRKO). No changes in reproductive development or function were observed in lean Cyp17IRKO female mice, suggesting that insulin signaling in TI cell is not essential for reproduction. However, when females were fed a high-fat diet, diet-induced obesity (DIO) wild-type (DIO-WT) mice were infertile and experienced increased circulating testosterone levels, whereas DIO-Cyp17IRKO mice exhibited improved fertility and testosterone levels comparable to those found in lean mice. The levels of phosphorylated IRS1 and CYP17 protein were higher in the ovary of DIO-WT compared with DIO-Cyp17IRKO or lean mice. Ex vivo studies using a whole ovary culture model demonstrated that insulin acts independently or additively with human chorionic gonadotropin to enhance androstenedione secretion. These studies reveal the causal pathway linking hyperinsulinism with ovarian hyperandrogenism and the infertility of obesity.     

肠道菌群在多囊卵巢综合征中作用的研究进展

多囊卵巢综合征(PCOS)是育龄期女性最常见的生殖内分泌疾病,主要特征为排卵功能障碍、卵巢多囊样改变和高雄激素血症。此外,临床上PCOS还常伴随肥胖和胰岛素抵抗。PCOS的临床特征具有复杂性和异质性,其发病机制一直是该领域的研究热点。近年来多项研究发现,PCOS发生发展与肠道菌群密切相关。在PCOS患者以及多种PCOS动物模型中,肠道菌群均发生改变,而菌群的改变与雌、雄激素水平、免疫和代谢异常有一定相关性。因此,本文主要从性激素合成、免疫和代谢三个方面阐述肠道菌群参与PCOS发生发展过程的分子机制,以期为PCOS的诊断和治疗提供一定参考。     

Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation

Most lifestyle-related chronic diseases are characterized by low-grade systemic inflammation and insulin resistance. Excessive tumor necrosis factor-alpha (TNF-alpha) concentrations have been implicated in the development of insulin resistance, but direct evidence in humans is lacking. Here, we demonstrate that TNF-alpha infusion in healthy humans induces insulin resistance in skeletal muscle, without effect on endogenous glucose production, as estimated by a combined euglycemic insulin clamp and stable isotope tracer method. TNF-alpha directly impairs glucose uptake and metabolism by altering insulin signal transduction. TNF-alpha infusion increases phosphorylation of p70 S6 kinase, extracellular signal-regulated kinase-1/2, and c-Jun NH(2)-terminal kinase, concomitant with increased serine and reduced tyrosine phosphorylation of insulin receptor substrate-1. These signaling effects are associated with impaired phosphorylation of Akt substrate 160, the most proximal step identified in the canonical insulin signaling cascade regulating GLUT4 translocation and glucose uptake. Thus, excessive concentrations of TNF-alpha negatively regulate insulin signaling and whole-body glucose uptake in humans. Our results provide a molecular link between low-grade systemic inflammation and the metabolic syndrome.     

Mechanisms linking gut microbial metabolites to insulin resistance

Insulin resistance is the rate-limiting step in the development of metabolic diseases, including type 2 diabetes. The gut microbiota has been implicated in host energy metabolism and metabolic diseases and is recognized as a quantitatively important organelle in host metabolism, as the human gut harbors 10 trillion bacterial cells. Gut microbiota break down various nutrients and produce metabolites that play fundamental roles in host metabolism and aid in the identification of possible therapeutic targets for metabolic diseases. Therefore, understanding the various effects of bacterial metabolites in the development of insulin resistance is critical. Here, we review the mechanisms linking gut microbial metabolites to insulin resistance in various insulin-responsive tissues.     

Vitamin D, the renin-angiotensin system, and insulin resistance

Insulin resistance is characterized by the systemic impairment of insulin action and is usually the result of aging, obesity, chronic inflammation, or another factor that may contribute to the inhibition of the insulin signaling pathway. Insulin resistance is accompanied by defects in lipid metabolism and blood coagulation, hypertension, obesity, and vascular inflammation in a syndrome called syndrome X or metabolic syndrome. Metabolic syndrome is involved in the development of atherosclerosis with consequent cardiovascular complications including acute myocardial infarction, stroke, and vascular disease. Recent data have shown that vitamin D acts as a negative regulator of the renin gene and that vitamin D deficiency is followed by increased renin-angiotensin II expression. The link between the insulin signaling pathway/insulin resistance and the renin-angiotensin system has been well documented in previous studies. The present review focuses on disorders characterized by a reduction in vitamin D concentration or its receptor function and the development of insulin resistance or metabolic syndrome, and discusses also possible therapeutic interventions.