Biochemical and Genetic Markers of Type 2 Diabetes Risk

描述（由申请人提供）：本更新申请旨在扩展我们在护士健康研究中对2型糖尿病（DM）预测因子的前瞻性评价，这是一项大型前瞻性队列研究，包含存档的血液标本。2型糖尿病是一个重大且日益严重的公共卫生问题，影响至少1700万美国人。肥胖与2型糖尿病的风险密切相关，但肥胖导致2型糖尿病的机制尚不确定。最近的证据表明，“脂肪因子”，包括瘦素及其受体、酰化刺激蛋白（ASP）、脂联素和游离脂肪酸（FFA），都是由脂肪组织分泌的，在2型糖尿病的发病机制中起作用。 DM.我们建议研究1）这些脂肪因子和FFA的血浆水平作为2型糖尿病发病的预测因子的作用，以及2）在调节脂肪因子和FFA代谢途径中重要的特定遗传变异体的关联，包括瘦素受体、β-内酰胺酶、IL-6、脂肪酸结合蛋白2和4（FABP 2、FABP 4）、CD 36和过氧化物酶体增殖物激活受体γ共激活因子-1（PGC 1），具有2型DM的风险。遗传学研究将针对基因编码区的假定功能变异，并将调查每个基因座的祖先单倍型与2型糖尿病风险之间的关联。我们还将研究特定的基因-环境相互作用（包括饮食，运动和肥胖本身的作用）和2型糖尿病的风险。阐明脂肪因子、FFA、其遗传决定因素、生活方式风险因素和2型DM发展之间的相互关系可能提示新的治疗和/或预防策略。该队列的先前工作有助于阐明体脂及其分布、体力活动水平、饮食因素和炎症作为2型DM决定因素的主要作用。我们试图通过在现有数据库中进行嵌套病例对照分析来建立这项工作，该数据库包括121，700名年龄在35-55岁的美国女护士，在1989-90年提供血液样本的32，825名妇女中，有1，275例2型糖尿病事件病例的随访和记录。这项已建立的队列研究的独特特征，包括其前瞻性设计，大规模，长时间，高随访率（超过90%，超过28年），储存血液标本的可用性和成本效益，使该数据库成为女性2型糖尿病病因学研究中无与伦比的资源。

DESCRIPTION (provided by applicant): This renewal application seeks to extend our prospective evaluation of predictors of type 2 diabetes mellitus (DM) in the Nurses' Health Study, a large prospective cohort with archived blood specimens. Type 2 DM is a major and increasing public health problem, affecting at least 17 million Americans. Obesity is strongly associated with risk for type 2 DM, yet mechanisms whereby obesity causes type 2 DM are uncertain. Recent evidence implicates "adipokines", including leptin and its receptors, acylation-stimulating protein (ASP), resistin, and adiponectin, and free fatty acids (FFA), all secreted by adipose tissue, in the pathogenesis of type 2 DM. We propose to study 1) the role of plasma levels of these adipokines and FFA as predictors of incident Type 2 DM, and 2) the association of specific genetic variants important in regulating adipokine and FFA metabolic pathways, including leptin receptor, resistin, IL-6, fatty acid binding proteins 2 and 4 (FABP2, FABP4), CD36, and peroxisome proliferators-activated receptor gamma coactivator- 1 (PGC 1), with risk of type 2 DM. Genetic studies will target putative functional variants in gene coding regions, and will also investigate associations between ancestral haplotypes at each locus and type 2 DM risk. We will also examine specific gene-environment interactions (including the role of diet, exercise, and obesity itself) and risk of type 2 DM. Elucidation of interrelationships among adipokines, FFA, their genetic determinants, lifestyle risk factors, and development of type 2 DM may suggest new treatment and/or prevention strategies. Previous work in this cohort has contributed to clarifying the major roles of body fat and its distribution, physical activity level, dietary factors, and inflammation as determinants of type 2 DM. We seek to build on this body of work by conducting nested case-control analyses in an existing database that includes 121,700 U.S. female nurses aged 35-55 at baseline, with follow-up and documentation through 2004 of 1,275 incident cases of type 2 DM among the 32,825 women who provided a blood sample in 1989-90. The unique features of this established cohort study, including its prospective design, large size, long duration, high follow-up rates (exceeding 90 percent over 28 years), availability of stored blood specimens, and cost-efficiency, make this database an unparalleled resource in the etiologic study of type 2 DM in women.