EFFECTS OF INSULIN SENSITIZERS OF BETA CELL FUNCTION AND LIPOTOXICITY

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。发展为2型糖尿病代表着一种进化，这是一种恶性循环的结果，糖毒性和脂毒性都会减少胰岛素的分泌和胰岛素的作用。脂毒性是一个新的概念，指的是非脂肪组织中脂质的过度积聚，反映了游离脂肪酸输送的增加。在动物模型中，骨骼肌和胰岛细胞脂肪含量的增加分别与胰岛素抵抗和胰岛细胞功能受损有关。在人类中，脂肪毒性是否是肥胖和糖尿病之间的联系，以及减少细胞内脂肪含量是否会改善人类的胰岛素分泌和敏感性尚不清楚。在这项研究中，我们将重点关注尚未出现葡萄糖毒性的糖耐量受损(IGT)肥胖者。我们将检测两种不同作用模式的胰岛素增敏剂对胰岛素分泌、胰岛素作用、肝脏葡萄糖生成和肌肉脂肪代谢的影响。我们认为，噻唑烷二酮类化合物可以通过逆转脂肪毒性来改善细胞功能，因为这反映了肌肉脂肪堆积的减少。

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. The progression to type 2 diabetes represents an evolution, which results from a vicious cycle where both glucotoxicity and lipotoxicity act to reduce insulin secretion and insulin action. Lipotoxicity is a new concept, which refers to overaccumulation of lipids in non-adipose tissue reflecting increased free fatty acid delivery. Increased fat content of skeletal muscle and islet cell is associated with insulin resistance and impaired pancreatic ¿-cell function respectively in animal models. Whether lipotoxicity is the link between obesity and diabetes, in humans, and whether reducing intracellular fat content will improve insulin secretion and sensitivity in humans is not known. In this study, we will focus on obese subjects with impaired glucose tolerance (IGT)* who have not yet developed glucose toxicity. We will examine insulin secretion, insulin action, hepatic glucose production, and muscle lipid metabolism in response to two insulin sensitizers with two different modes of action. We propose that thiazolidinediones will improve ¿ cell function by reversing lipotoxicity as reflective in reduced muscle lipid accumulation.