Steroid Hormones, Adipose-cytokines, and Diabetes Risk

描述(申请人提供)：肥胖和胰岛素抵抗是2型糖尿病(DM)发病机制的基本特征。新出现的数据表明，性类固醇激素和脂肪细胞衍生的激素和细胞因子(“脂肪因子”)可能与2型糖尿病的风险有关，其中一些新的标记物可能与这种风险表现出性别二型性。在两个有存档血液样本的男性和女性的大型前瞻性队列中，我们建议调查内源性类固醇激素和脂肪因子在2型糖尿病发展中的作用。在妇女健康研究(WHS)的12,304名女性和医生健康研究II(PHS II)的11,130名男性中，总共将识别和确认1200例2型糖尿病病例。我们将检测五种类固醇激素(即总的和生物可利用的睾酮、雌二醇-17β[E_2]、脱氢表雄酮硫酸盐[DHEAS]和性激素结合球蛋白[SHBG])，以及三种脂肪因子(肿瘤坏死因子-α[TNF]、脂联素和抵抗素)。使用冰冻血浆样本可以可靠地测量这些生化标记物。应用最先进的基因分型技术和统计学方法，我们将定义功能变异，确定9个相关候选基因的单倍型结构，并评估它们作为2型糖尿病风险预测因子的作用。这些基因将包括激素代谢基因(芳香酶[CYP19]、雄激素受体、雌激素受体α[ESR1]和SHBG)，以及与肥胖和胰岛素抵抗相关的基因(即过氧化体增殖物激活受体-伽马[PPARGamma]和响应PPAR3‘信号的基因，包括TNFpha、脂联素、抵抗素和脂肪细胞-脂肪酸结合蛋白[aP2])。阐明这些新的生化和遗传标记与2型糖尿病的发展之间的相互关系可能有助于识别高危个体并提出新的治疗和/或预防策略，其中一些可能是针对性别的。这些已建立的队列研究的几个独特特点，包括它们相同的前瞻性设计和数据收集程序、高随访率、储存血液样本的可用性和成本效益，使这些人群成为研究女性和男性2型糖尿病病因的特殊资源。

DESCRIPTION (provided by applicant): Adiposity and insulin resistance are fundamental features in the pathogenesis of type 2 diabetes mellitus (DM). Emerging data suggest that sex-steroid hormones and adipocyte-derived hormones and cytokines ("adipokines") may be associated with type 2 DM risk and that some of these novel markers may exhibit a sexual dimorphism with respect to this risk. In two large prospective cohorts of men and women with archived blood specimens, we propose to investigate the roles of endogenous steroid hormones and adipokines in the development of type 2 DM. A total of 1,200 incident eases of type 2 DM will be identified and confirmed among 12,304 women in the Women's Health Study (WHS) and 11,130 men in the Physicians' Health Study II (PHS II). We will assay five steroid hormones (i.e., total and bioavailable testosterone, estradiol-17beta [E2], dehydroepiandrosterone sulfate [DHEAS], and sex hormone binding globulin [SHBG]), and three adipokines (tumor necrosis factor-alpha [TNF], adiponectin, and resistin). These biochemical markers can be reliably measured using frozen plasma samples. Applying state-of-the-art genotyping technology and statistical methods, we will define functional variants and determine the structure of haplotypes in nine relevant candidate genes and evaluate their roles as predictors for risk of type 2 DM. These genes will include hormone-metabolizing genes (aromatase [CYP19], androgen receptor, estrogen receptor alpha [ESR1], and SHBG), as well as those related to adiposity and insulin resistance (i.e., peroxisome proliferator-activated receptor-gamma [PPARgamma] and genes that respond to PPAR3' signaling, including TNFalpha, adiponectin, resistin, and the adipocyte-fatty acid binding protein [aP2]). Elucidation of interrelationships between these novel biochemical and genetic markers and the development of type 2 DM may help identify high risk individuals and suggest new treatment and/or prevention strategies, some of which may be sex-specific. Several unique features of these established cohort studies, including their identical prospective design and data collection procedures, high follow-up rates, availability of stored blood specimens, and cost efficiency, make these populations exceptional resources for the etiologic investigation of type 2 DM in women and men.