Steroid Hormones, Adipose-cytokines, and Diabetes Risk

类固醇激素、脂肪细胞因子和糖尿病风险

• 批准号: 6898886
• 负责人: Simin Liu
• 金额: $ 15.34万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2005-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6898886
• 关键词: adipocytes; clinical research; cytokine; dehydroepiandrosterone; diabetes mellitus genetics; diabetes risk; disease /disorder etiology; estradiol; gender difference; genetic markers; genetic screening; genetic susceptibility; genotype; hormone binding protein; hormone regulation /control mechanism; human middle age (35-64); human old age (65+); human subject; insulin sensitivity /resistance; noninsulin dependent diabetes mellitus; obesity; pathologic process; patient oriented research; postmenopause; sex hormones; testosterone; tumor necrosis factor alpha

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.

描述（由申请人提供）：肥胖和胰岛素抵抗是2型糖尿病（DM）发病机理中的基本特征。新兴的数据表明，性肌动感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DM风险有关，并且其中一些新颖的标记物可能在这种风险方面表现出性二态性。在两个大型前瞻性人群中，有存档的血标本，我们建议研究内源性类固醇激素和脂肪因子在2型DM开发中的作用。在妇女健康研究（WHS）中，将在12,304名妇女中确定并确认总共1,200起事件，并在医师健康研究II（PHS II）中确认并确认11,130名男性。我们将测定五种类固醇激素（即总和可生物可利用睾丸激素，雌二醇-17beta [E2]，脱氢表二甲二甲二硫酸硫酸盐[DHEAS]和性激素结合球蛋白[SHBG]）和三个脂肪因子和三个脂肪因子（肿瘤坏死因子 - alpha-alpha-Alpha [Tnfin）和Adiponcin，and adiponcin，and adiponcin，and adiponectin，and diponectin。这些生化标记可以使用冷冻血浆样品可靠地测量。采用最先进的基因分型技术和统计方法，我们将定义功能变体，并确定九个相关候选基因中的单倍型的结构，并评估其作为2型DM风险的预测指标。这些基因将包括激素量代谢基因（芳香酶[CYP19]，雄激素受体，雌激素受体α[ESR1]和SHBG），以及与脂肪和胰岛素耐药性有关的基因（即过氧化物酶体增殖物激活受体激活的受体gamma [ppargamma]和Genses the paryf，脂联素，抗素和脂肪细胞脂肪酸结合蛋白[AP2]）。阐明这些新型生化和遗传标志物与2型DM的发展之间的相互关系可能有助于识别高风险个人，并建议新的治疗方法和/或预防策略，其中一些可能是特定于性别的。这些已建立的队列研究的几个独特特征，包括它们相同的前瞻性设计和数据收集程序，高后续率，储存的血液标本的可用性以及成本效率，使这些人群为男女2型DM的病因学研究提供了出色的资源。