Insulin Resistance in Adolescents at High Risk for PCOS

描述(由申请者提供)：申请者之前的重点是 类固醇激素生物合成的分子方面研究。他最近 担任加州大学洛杉矶分校医学院儿科学助理教授 医学。为了进一步发展他的职业生涯，作为一名独立调查员，他 与卵巢生理学领域的专家建立了关系， 胰岛素信号、敏感性和分泌。在他们的指导下 监督，候选人将启动研究，以解决童年问题 多囊卵巢综合征(PCOS)的起源。PCOS是一种异质的 以青春期后月经开始为特征的临床实体 男性荷尔蒙分泌不规律和过度分泌。PCOS是最多的 育龄妇女常见的内分泌紊乱，影响5%-10% 世界各地的女性。胰岛素抵抗是两种2型糖尿病的必要先兆 糖尿病(T2 DM)和以多囊卵巢综合征为特征的激素失衡。 由于胰岛素抵抗是正常青春期的短暂生理现象 成熟时，申请者假设必要的胰岛素抵抗 在青春期发育过程中，PCOS基因最初必须表达。克罗斯- 部分和纵向研究将描述胰岛素的模式。 年轻女性在整个青春期都表现出的敏感。最初， 申请者将对比频繁采样的胰岛素敏感性 两组25人之间的静脉(Iv)葡萄糖耐量试验 受试者分别来自有多囊卵巢综合征病史和无多囊卵巢综合征病史的家庭 青春期的不同阶段。然后，他将测试胰岛素的假设 40名高危女孩的抵抗力在青春期期间的演变 多囊卵巢综合征的发展在质量和数量上都有不同的模式 与同等数量的青少年对照组相比，儿童的表情变化更明显。这个 申请者将测量特定的生物物理和生化参数以 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 这种独特形式的胰岛素抵抗的机制，申请人还 建议从SELECT获得胰岛素反应肌肉的针刺活检 在交叉试验中表现出极端胰岛素敏感性的受试者- 横断面研究。申请人将评估以下各项的完整性和功能 胰岛素信号的细胞传递所需的特定分子， 来确定这些效应器的变化是否可能是 高危人群中胰岛素抵抗的演变。这项工作将提供 对多囊卵巢综合征和胰岛素抵抗之间最早关系的洞察，请参见 全身和细胞水平。增强了对这些基本原理的理解 事件可能允许更早的检测和干预，从而防止 与多囊卵巢综合征相关的T2 DM的深刻生理后果。

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.