Insulin Resistance in Adolescents at High Risk for PCOS

描述（由申请人提供）：申请人以前专注于他的 类固醇激素生物合成的分子方面的研究。他最近 在加州大学洛杉矶分校儿科学院担任助理教授， 药作为一名独立调查员，为了进一步发展自己的职业生涯， 与卵巢生理学领域的专家建立了联系， 胰岛素信号传导、敏感性和分泌。在他们的指导下， 监督，候选人将启动研究，以解决儿童 多囊卵巢综合征（PCOS）的病因PCOS是一种异质性 以青春期后月经开始为特征的临床实体 不规则和雄性激素的过度分泌。PCOS是最 育龄妇女常见的内分泌失调，影响5-10%的 全世界的女人。胰岛素抵抗是2型糖尿病和2型糖尿病的必要前提。 糖尿病（T2 DM）和PCOS的激素失衡特征。 由于胰岛素抵抗是正常青春期短暂的生理现象， 在成熟的情况下，申请人假设必需的胰岛素抵抗 多囊卵巢综合征的发病最初必须在青春期进展期间表达。交叉- 横断面和纵向研究将描述胰岛素的模式， 在青春期出现的敏感性。最初 申请人将对比频繁采样的胰岛素敏感性 静脉（iv）葡萄糖耐量试验之间的两个匹配的集25 受试者来自有或没有PCOS病史的家庭，在两个 青春期的不同阶段 然后他将检验胰岛素 40名高危女孩在整个青春期的抵抗力演变 多囊卵巢综合征的发展在质和量上不同， 表达，与同等数量的青少年对照相比。 的 申请人将测量特定的生物物理和生物化学参数， 确定这些容易获得的指数的变化是否与 预测胰岛素敏感性的变化。 为了开始阐明细胞 对于这种独特形式的胰岛素抵抗的机制，申请人进一步 建议从选择的患者中获得胰岛素反应性肌肉的针吸活检， 在交叉试验中表现出极端胰岛素敏感性的受试者- 分段研究 申请人将评估的完整性和功能 胰岛素信号的细胞传递所必需的特定分子， 以确定这些效应器的变化是否可能导致 在高危人群中发展胰岛素抵抗。这项工作将提供 了解PCOS和胰岛素抵抗之间的最早关系， 全身和细胞水平。加强对这些基本问题的认识 事件可能允许更早的检测和干预，从而防止 与PCOS相关的T2 DM未缓解的严重生理后果。

DESCRIPTION (provided by applicant): The applicant previously focused his research on molecular aspects of steroid hormone biosynthesis. He recently assumed a position as Assistant Professor of Pediatrics in the UCLA School of Medicine. To further his career, as an independent investigator, he has established relationships with experts in the fields of ovarian physiology, insulin signaling, sensitivity and secretion. Under their mentored supervision, the candidate will initiate studies to address the childhood origins of the polycystic ovary syndrome (PCOS). PCOS is a heterogeneous clinical entity characterized by the post-pubertal onset of menstrual irregularities and excessive production of male hormones. PCOS is the most common endocrine disorder of women of reproductive age, affecting 5-10% of women worldwide. Insulin resistance is a necessary antecedent of both type 2 diabetes mellitus (T2DM) and the hormonal imbalances characteristic of PCOS. As insulin resistance is a transient physiologic phenomenon of normal pubertal maturation, the applicant hypothesizes that the requisite insulin resistance of PCOS must be expressed initially during pubertal progression. Cross- sectional and longitudinal studies will describe the patterns of insulin sensitivity that emerge throughout puberty in young women. Initially, the applicant will contrast the insulin sensitivity achieved on frequently sampled intravenous (iv) glucose tolerance tests between two matched sets of 25 subjects from families with, and without, histories of PCOS, at each of two distinct stages of puberty. He will then test the hypothesis that insulin resistance evolving throughout puberty in 40 girls at high risk for development of PCOS differs qualitatively and quantitatively in its pattern of expression, when compared with an equal number of adolescent controls. The applicant will measure specific biophysical and biochemical parameters to determine whether changes in these easily-obtained indices correlate with and predict changes in insulin sensitivity. To begin to elucidate the cellular mechanism for this unique form of insulin resistance, the applicant further proposes to obtain needle biopsies of insulin-responsive muscle from select subjects who demonstrate extremes of insulin sensitivity in the cross- sectional study. The applicant will assess the integrity and function of specific molecules necessary for cellular transmission of the insulin signal, to determine whether changes in these effectors might be responsible for evolving insulin resistance in at-risk individuals. This work will provide insight into the earliest relationship between PCOS and insulin resistance, at the whole-body and cellular level. Enhanced understanding of these fundamental events may permit earlier detection and intervention, thus preventing the profound physiological consequences of unabated T2DM associated with PCOS.