Development of Diabetic Cardiomyopathy in GLUT4 +/- Mice

描述：(从申请人的摘要中扫描)小鼠有一只 低脂饮食中GLUT4(+/-)基因敲除等位基因与II型糖尿病的关系 包括高胰岛素血症、高血糖、高瘦素血症、轻度高血压、 心肌病和肝脏脂肪变性随年龄增长。这些病理现象会发生 不受肥胖、血脂异常、胰腺衰竭和肝脏胰岛素的影响 抵抗。我们建议进行第一个体内纵向研究， 检查导致糖尿病的关键分子/代谢/能量变化 心肌病。这解决了整个身体之间的重要相互作用 调节细胞过程的新陈代谢和循环因子 导致终末器官病理。中心假设是全球减少 GLUT4表达和/或功能导致心脏胰岛素改变 细胞因子减少所介导的作用、葡萄糖代谢和能量学 PPAR-γ和Akt/PKB活性导致收缩功能改变 和糖尿病心肌病。改变底物的使用，并增加对 脂肪酸代谢与氧化应激增加和 线粒体解偶联，导致能量储备减少。胰岛素 用活化的噻唑烷二酮(TZD)BRL49653治疗增敏剂 PPARG，通过以下途径改善全身血糖稳态和心功能 AktJPKB活性、底物利用和解偶联蛋白表达的变化 蛋白质(UCP)和葡萄糖转运蛋白(GLUT)基因/蛋白质。这些研究将 提供对分子、代谢和形态变化的独特见解 在GLUT4+/-心脏中，随着小鼠进展为糖尿病，这应该会促进 预防和/或减少糖尿病心肌病的治疗方法的发展 在人类身上。 为了实现这些目标，我们有四个具体目标。每个目标都将确定 Akt/PKB、GLUT4-和GLUTx1易位对胰岛素作用的影响 底物分配/转运与GLUT和UCP2/3基因/蛋白表达 在GLUT4+/-组和对照组小鼠心脏中。分子和细胞分析将是 与心脏形态和血流动力学改变及心脏血管病变的相关性 全身血糖稳态和循环血清因子(如瘦素， 胰岛素、T3/T4、葡萄糖、游离脂肪酸)作为小鼠从正常(N/N)的进展 从糖尿病前期(N/H)到显性糖尿病(H/H)表型。短期影响 使用TZD BRL49653(PPARg激动剂)对这些参数的治疗将是 在体重或肥胖发生重大变化之前被定义为 量过了。后一项研究将确定TZDS的作用机制。 并可能揭示新的治疗靶点和应用。

DESCRIPTION: (Scanned from the applicant's abstract) Mice with a single knockout allele of GLUT4(+/-) on a low fat diet develop type II diabetes including hyperinsulinemia, hyperglycemia, hyperleptinemia, mild hypertension, cardiomyopathy and liver steatosis with age. These pathologies occur independent of obesity, dyslipidemia, pancreatic failure and hepatic insulin resistance. We propose to conduct the first in vivo longitudinal study which examines critical molecular/metabolic/energetic alterations leading to diabetic cardiomyopathy. This addresses the important interplay between whole body metabolism and circulating factors that regulate cellular processes which result in end organ pathology. The central hypothesis is global reduction of GLUT4 expression and/or function leads to alterations in cardiac insulin action, glucose metabolism and energetics mediated by reductions in the activity of PPARgamma and Akt/PKB which result in altered contractile function and diabetic cardiomyopathy. Altered substrate use with increased reliance upon fatty acid metabolism is associated with increased oxidative stress and mitochondrial uncoupling that result in diminished energy reserves. Insulin sensitizer treatment with BRL49653, a thiazolidinedione (TZD) that activates PPARg, will improve whole body glucose homeostasis and cardiac function through alterations in AktJPKB activity, substrate usage and expression of uncoupling protein (UCP) and glucose transporter (GLUT) genes/proteins. These studies will provide unique insight into molecular, metabolic, and morphologic alterations in GLUT4+/- hearts as mice progress to diabetes that should facilitate development of therapeutics to prevent and/or minimize diabetic cardiomyopathy in humans. To accomplish these goals we have four specific aims. Each aim will identify alterations in insulin action through Akt/PKB, GLUT4- and GLUTx1 translocation, substrate partitioning/trafficking, and GLUT and UCP2/3 gene/protein expression in hearts of GLUT4+/- and control mice. Molecular and cellular analyses will be correlated with morphologic and hemodynamic changes in heart and alterations in whole body glucose homeostasis and circulating serum factors (e.g. leptin, insulin, T3/T4, glucose, free fatty acids) as mice progress from normal (N/N) to prediabetic (N/H) to overt diabetic (H/H) phenotypes. Effects of short term treatment with the TZD BRL49653 (PPARg agonist) on these parameters will be defined before significant alterations in body weight or adiposity can be measured. The latter studies will determine the mechanism of action of TZDs in the heart and may reveal novel therapeutic targets and applications.