ATHEROSCLEROSIS IN INSULIN-RESISTANT, HYPERLIPIDEMIC PTS

描述(由申请人提供)： II型胰岛素抵抗(IR)糖尿病患者的原因不明 与糖尿病相比，糖尿病患者动脉粥样硬化的发生率更高 非糖尿病患者。我们的目标是开发IR的猪模型和混合模型 IR和家族性高胆固醇血症的关系，这将有助于研究 明确IR在动脉粥样硬化中的作用。这些猪将被用来确定 如果IR的存在导致动脉粥样硬化负担增加，与 对照没有IR的动物，并确定动脉粥样硬化的标志物 在这些动物中的存在将与疾病的进展相关 我是动物。将使用两种独特的猪品种，其中一种来自教堂山(CH) 全身脂肪增加，第二个有家族性高胆固醇血症 (Fh)瘦的。CH和FH毒株都有带和的亚群 不增加胰岛素抵抗(IR)。在AIM I中，CH-IR和FH-IR猪将 为增加IR的严重程度而饲养。在AIM II中，IR对 冠状动脉、主动脉和颈动脉粥样硬化程度及其变化 血清和组织中动脉粥样硬化的标记物将在CH-IR中测定 并与没有IR的CH猪进行比较，两组都饲喂高脂肪 致动脉粥样硬化饮食。第二项研究将在FH-IR中比较这些相同的变量 FH-非IR猪饲喂正常(低脂)猪饲料。血管内超声 (IVUS)将在研究期间用于监测体内的疾病进展。 将使用IVUS和固定血管的形态测量来测量 终末期动脉粥样硬化。在AIM III中，胰岛素样生长因子-I 给CH-IR猪注射胰岛素样生长因子-1(IGF-1)以降低IR，并对猪进行饲养 导致动脉粥样硬化的高脂肪饮食。动脉粥样硬化的程度和动脉粥样硬化的变化 这些接受IGF-I治疗的猪的标志物将与对照组进行比较。在目标四中， FH-IR猪将饲喂正常(低脂)猪饲料和aVb3抑制剂 我们已经显示了减少非胰岛素抵抗猪的动脉粥样硬化及其对 损伤发展已确定。我们的总体目标是开发一种有用的、 相关的、可用的IR和动脉粥样硬化模型，可用于 确定胰岛素导致动脉粥样硬化加速的机制 对人类产生抗药性，并开发和测试潜在的新治疗策略。

DESCRIPTION (provided by applicant): It is unknown why patients with type II insulin resistant (IR) diabetes mellitus have an increased incidence of atherosclerosis when compared to non-diabetics. Our goal is to develop porcine models of IR and a mixed model of IR plus familial hypercholesterolemia that will be useful in studies to define the role of IR in atherosclerosis. The pigs will be used to determine if the presence of IR causes an increased burden of atherosclerosis compared to control animals without IR and to determine if markers of atherosclerosis that are present in these animals will correlate with disease progression in IR animals. Two unique strains of pigs will be used, one from Chapel Hill (CH) with increased total body fat and a second with familial hypercholesterolemia (FH) that are lean. Both the CH and FH strains have subpopulations with and without increased insulin resistance (IR). In Aim I, CH-IR and FH-IR pigs will be bred for increased severity of IR. In Aim II, the effect of IR on the extent of coronary, aortic, and carotid artery atherosclerosis and the changes in serum and tissue markers of atherosclerosis will be determined in CH-IR pigs and compared to CH pigs without IR, both groups being fed a high fat atherogenic diet. A second study will compare these same variables in FH-IR and FH-nonIR pigs fed normal (low fat) pig chow. Intravascular ultrasound (IVUS) will be used during the study to monitor disease progression in vivo. Both IVUS and morphometry of fixed vessels will be used to measure atherosclerosis at termination. In Aim III, insulin like growth factor-I (IGF-1) will be given to the CH-IR pigs to reduce IR, and the pigs will be fed a high fat atherogenic diet. The extent of atherosclerosis and the changes in markers in these IGF-I treated pigs will be compared to controls. In Aim IV, the FH-IR pigs will be fed normal (low fat) pig chow and an aVb3 inhibitor that we have shown reduces atherosclerosis in non-IR pigs and its effect on lesion development determined. Our overall objective is to develop a useful, relevant, available model of IR and atherosclerosis that can be used to identify mechanisms that lead to accelerated atherosclerosis in insulin resistant humans and to develop and test potential new treatment strategies.