EFFECTS OF INSULIN SENSITIZERS OF BETA CELL FUNCTION AND LIPOTOXICITY

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。发展为2型糖尿病代表了一种演变，这是由恶性循环引起的，其中葡萄糖毒性和脂毒性都起到减少胰岛素分泌和胰岛素作用的作用。脂毒性是一个新的概念，它是指脂质在非脂肪组织中的过度积累，反映了游离脂肪酸的释放增加。在动物模型中，骨骼肌和胰岛细胞脂肪含量增加分别与胰岛素抵抗和胰腺细胞功能受损相关。脂毒性是否是人类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胰岛素分泌和敏感性尚不清楚。在本研究中，我们将重点关注尚未发生葡萄糖毒性的糖耐量受损（IGT）* 肥胖受试者。我们将研究胰岛素分泌，胰岛素的作用，肝葡萄糖的生产，和肌肉脂质代谢的两种胰岛素增敏剂与两种不同的作用模式。我们认为噻唑烷二酮类药物通过逆转脂肪毒性来改善细胞功能，这反映了肌肉脂质积累减少。

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.