Inflammation: Effect on Insulin Resistance in PCOS

描述（由申请人提供）：多囊卵巢综合征（PCOS）是一种病因不明的内分泌疾病，影响多达8%的女性人口，是女性不育的最常见原因。多囊卵巢综合征的慢性无排卵和高雄激素症特征是由胰岛素抵抗和由此导致的高胰岛素血症在大多数患者中传播的。胰岛素抵抗使患者易患2型糖尿病，也是心血管疾病早期发病的已知危险因素。肿瘤坏死因子α (tnf - α)是一种由脂肪组织和活化的单核细胞（MNC）产生的炎症细胞因子，被认为是多囊卵巢综合征胰岛素抵抗的中介。拟议的研究将包括对40名育龄妇女（18-40岁）的前瞻性研究。20名女性将患有多囊卵巢综合征（10名体重正常，10名肥胖），20名女性将进行体重匹配的排卵控制。中心假设是生理性碳水化合物挑战触发多囊卵巢综合征妇女MNC过度释放tnf - α。具体目的是：1)检测多囊卵巢综合征女性MNC中tnf - α释放对葡萄糖刺激的响应；2)探讨PCOS女性MNC对葡萄糖刺激的炎症通路。该方法使用从空腹血液样本中分离的培养的MNC，对PCOS女性在标准口服葡萄糖激发试验中体内葡萄糖暴露前后以及在血糖正常和高血糖状态下的MNC培养上清中tnf - α释放量进行量化。通过测定[活性氧]ROS的生成、炎症通路蛋白标记物和活化核因子κ B （NFkB）的表达，评估PCOS女性MNC在体内葡萄糖刺激前后的炎症反应。我们期望在这项研究中使用的方法将证明过度的跨国公司衍生的tnf - α释放和葡萄糖刺激后明显的炎症反应。这些结果将具有重要意义，因为它们将确定除了脂肪组织外，MNC是PCOS中过量tnf - α的另一个来源，以及MNC中过量tnf - α释放的炎症机制。这将导致PCOS治疗的重要进展，旨在通过减少炎症来改善胰岛素抵抗。这也将为未来研究确定MNC对PCOS女性餐后高血糖敏感的分子机制提供优先考虑，使这些个体处于促炎状态。

DESCRIPTION (provided by applicant): Polycystic Ovary Syndrome (PCOS) is an endocrinopathy of unknown etiology that affects as many as 8% of the female population and is the most common cause of female infertility. The chronic anovulation and hyperandrogenism characteristic of PCOS is promulgated by insulin resistance and the resultant hyperinsulinemia in the majority of affected individuals. The insulin resistance predisposes those with the disorder to type 2 diabetes and is a known risk factor for early onset of cardiovascular disease. Tumor necrosis factor alpha (TNF-alpha), an inflammatory cytokine produced by adipose tissue and activated mononuclear cells (MNC) has been implicated as a mediator of insulin resistance in PCOS. The proposed research will involve the perspective study of 40 reproductive age women (18-40 years). Twenty of the women will have PCOS (10 normal weight and 10 obese) and 20 will be weight-matched ovulatory controls. The central hypothesis is that a physiologic carbohydrate challenge triggers excessive TNF-alpha release from MNC of women with PCOS. The specific aims are: 1) to examine TNF-alpha release from MNC of women with PCOS in response to glucose stimulation; 2) to examine the inflammation pathway in MNC of women with PCOS in response to glucose stimulation. The approach involves the quantification of TNF-alpha release from MNC culture supernatants of women with PCOS before and after in vivo glucose exposure during a standard oral glucose challenge test and under euglycemic and hyperglycemic conditions in vitro using cultured MNC isolated from fasting blood samples. The inflammatory response of MNC in women with PCOS will also be evaluated before and after in vivo glucose challenge by measuring [reactive oxygen species] ROS generation, expression of protein markers of the inflammation pathway and activated nuclear factor kappa B (NFkB). It is our expectation that the approach used in this study will demonstrate excessive MNC-derived TNF-alpha release and a pronounced inflammatory response following glucose stimulation. These results will be significant in that they will identify the MNC as an additional source of excess TNF-alpha in PCOS aside from adipose tissue, and the inflammatory mechanism responsible for excessive TNF-alpha release from MNC. This will lead to important advances in the therapy of PCOS designed to ameliorate insulin resistance by reducing inflammation. It will also provide precedence for future studies to determine the molecular mechanism responsible for the sensitivity of MNC to postprandial hyperglycemia in women with PCOS that places these individuals in a proinflammatory state.