SECRETED ADIPOCYTE PROTEINS, INSULIN RESISTANCE VASCULAR

描述：（申请人提供） 胰岛素抵抗综合征（IRS）增加心血管疾病的风险 糖尿病患者和非糖尿病患者。IRS的发展是 与腹部脂肪和腰臀比增加密切相关。我们的数据 表明异常NMR脂蛋白亚类谱与高 在1型糖尿病患者中，腰/臀和血管疾病风险增加。的 血脂异常模式与血糖正常IRS中观察到的模式相同， 2型糖尿病，可通过胰岛素增敏来预防 噻唑烷二酮类。腹部脂肪增加与生化指标之间的联系 IRS的风险因素尚不清楚。脂肪细胞分泌大量的 影响脂肪细胞大小和功能的旁分泌和内分泌因子， 以及全身生理学。项目5的总体目标是评估 第一次发现分泌的脂肪细胞蛋白质对生物化学的影响， 糖尿病和IRS的风险特征和心血管疾病事件。的 研究将涉及1型（DCCT/EDIC）和2型（VA）的独特国家队列 合作试验）糖尿病患者，结合体外研究，以 为了验证流行病学和机械学的特定假设， 视角在具体目标1中，我们将测量新的 脂肪细胞衍生的蛋白质，包括脂联素、酰化刺激 蛋白、CETP、PLTP、派-1、血管紧张素原和瘦素，并评估其 与心血管危险因素和临床事件的关系 糖尿病队列。在具体目标2中，我们将确定 噻唑烷二酮治疗2型糖尿病对分泌的脂肪细胞蛋白的影响， 生化风险和心血管事件。在具体目标3中， 我们将研究培养的脂肪细胞从胰岛素敏感，IRS，和2型 糖尿病患者，并评估脂肪细胞蛋白质的分泌速率， 直接评估循环水平的变化是否与 体外分泌率我们还将研究蛋白质分泌的调节， 底物、自分泌/旁分泌因子和噻唑烷二酮类。在特定 目的4，我们将研究是否特定的基因多态性影响分泌 脂肪细胞蛋白质与糖尿病患者心血管疾病风险的关系。这些 研究将确定分泌的脂肪细胞蛋白是否负责 IRS集群中的多个特征，以及IRS在介导 糖尿病患者患心血管疾病的风险增加。

DESCRIPTION: (provided by applicant) The Insulin Resistance Syndrome (IRS) augments risk for cardiovascular disease in patients both with and without diabetes. The development of the IRS is integrally coupled to increased abdominal fat and waist/hip ratio. Our data show that an abnormal NMR lipoprotein subclass profile is associated with high waist/hip and confers increased vascular disease risk in Type 1 diabetes. The dyslipidemic pattern is identical to that observed in normoglycemic IRS and Type 2 Diabetes, and can be reserved by insulin-sensitizing thiazolidinediones. The link between increased abdominal fat and biochemical risk factors in IRS is unknown. Adipocytes secrete a large number of paracrine and endocrine factors that influence adipocyte size and function as well as whole-body physiology. The overall goal of Project 5 is to assess for the first time the effects of secreted adipocyte proteins on the biochemical risk profile and cardiovascular disease events in diabetes and IRS. The studies will involve unique national cohorts of Type 1 (DCCT/EDIC) and 2 (VA Cooperative Trial) diabetic patients, combined with in vitro studies, in order to test specific hypotheses from both epidemiological and mechanistic perspectives. In Specific Aim 1 we will measure circulating levels of novel adipocyte-derived proteins including adiponectin, acylation stimulating protein, CETP, PLTP, PAI-1, angiotensinogen, and leptin, and assess their relationship with cardiovascular risk factors and clinical events in both diabetes cohorts. In Specific Aim 2, we will determine the effects of thiazolidinedione treatment in Type 2 Diabetes on secreted adipocyte proteins, the biochemical risk profile, and cardiovascular events. In Specific Aim 3, we will study cultured adipocytes from insulin sensitive, IRS, and Type 2 diabetics, and assess the secretion rate of adipocyte proteins in vitro to directly assess whether changes in circulating levels are correlated with in vitro secretion rates. We will also study regulation of protein secretion by substrates, autocrine/paracrine factors, and thiazolidinediones. In Specific Aim 4, we will examine whether specific gene polymorphisms influence secretion of adipocyte proteins and cardiovascular disease risk in diabetes. These studies will determine whether secreted adipocyte proteins are responsible for multiple traits in the IRS cluster, and the role of the IRS in mediating increased risk for cardiovascular disease in diabetes.