Development of Diabetic Cardiomyopathy in GLUT4 +/- Mice

描述：（扫描自申请人摘要） GLUT 4（+/-）敲除等位基因在低脂肪饮食下发展为II型糖尿病 包括高胰岛素血症、高血糖症、高瘦素血症、轻度高血压， 心肌病和肝脏脂肪变性。这些病理发生在 与肥胖、血脂异常、胰腺衰竭和肝胰岛素无关 阻力我们建议进行第一次体内纵向研究， 检查导致糖尿病的关键分子/代谢/能量改变 心肌病这解决了整个身体之间的重要相互作用 调节细胞过程的代谢和循环因子， 导致最终器官病理学。核心假设是全球减少 GLUT 4表达和/或功能导致心脏胰岛素水平改变 作用，葡萄糖代谢和能量介导的减少， 导致收缩功能改变的PPARgamma和Akt/PKB活性 和糖尿病心肌病。基质使用的改变， 脂肪酸代谢与增加的氧化应激有关， 线粒体解偶联导致能量储备减少。胰岛素 用BRL 49653（一种噻唑烷二酮（TZD）， PPARg将通过以下途径改善全身葡萄糖稳态和心脏功能： AktJPKB活性、底物使用和解偶联蛋白表达的改变 蛋白（UCP）和葡萄糖转运蛋白（GLUT）基因/蛋白。这些研究将 对分子、代谢和形态学改变提供独特的见解 在GLUT 4 +/-心脏中，小鼠进展为糖尿病， 开发预防和/或最小化糖尿病性心肌病的治疗剂 在人类身上。 为了实现这些目标，我们有四个具体目标。每个目标将确定 通过Akt/PKB、GLUT 4-和GLUTx 1易位改变胰岛素作用， 底物分配/运输以及GLUT和UCP 2/3基因/蛋白表达 在GLUT 4 +/-和对照小鼠的心脏中。分子和细胞分析将是 与心脏的形态学和血流动力学变化以及 全身葡萄糖稳态和循环血清因子（例如瘦素， 胰岛素、T3/T4、葡萄糖、游离脂肪酸），因为小鼠从正常（N/N） 糖尿病前期（N/H）至显性糖尿病（H/H）表型。短期影响 用TZD BRL 49653（PPARg激动剂）治疗对这些参数的影响将是 在体重或肥胖发生显著变化之前， 测定了后面的研究将确定TZD在以下方面的作用机制： 心脏，并可能揭示新的治疗目标和应用。

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.