EFFECTS OF INSULIN SENSITIZERS AND PPAR LIGANDS ON LIPOTOXICITY IN SUBJECTS WITH

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。肥胖与胰岛素抵抗和骨骼肌、胰腺和肝脏中脂肪堆积增加有关，由此导致的功能损害被称为脂毒性。导致异位脂肪堆积的因素以及逆转这一病理生理的最佳干预措施尚不清楚。我们将检测不同PPAR配体对糖耐量受损受试者的胰岛素敏感性、细胞内脂肪含量、脂肪因子的分泌和基因表达模式的变化。我们建议PPAR a配体(非诺贝特)和PPAR？配体(吡格列酮)分别通过刺激肌肉脂肪氧化和脂肪从肌肉到脂肪细胞的重新分布来减少肌肉脂肪堆积。这两种药物的组合在减少肌肉脂肪堆积方面将特别有效。这些研究旨在研究代谢综合征和糖尿病的基本临床机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity is associated with insulin resistance and increased lipid accumulation in skeletal muscle, pancreas, and liver, with resulting functional impairment that has been called lipotoxicity. The factors leading to ectopic lipid accumulation and the best intervention to reverse this pathophysiology are not clear. We will examine insulin sensitivity, intramyocellular fat content, adipokines secretion and changed in the pattern of gene expression in subjects with impaired glucose tolerance in response to different PPAR ligands. We propose that PPAR a ligand (fenofibrate) and PPAR ? ligand (pioglitazone) will reduce muscle lipid accumulation by stimulating muscle lipid oxidation and redistribution of lipid from muscle to adipocytes respectively. The combination of both medications will be particularly effective at reducing muscle lipid accumulation. These studies are designed to examine fundamental clinical mechanisms underlying the metabolic syndrome and diabetes.