PREDOCTORAL FELLOWSHIP FOR STUDENTS WITH DISABILITIES

描述(申请人提供)：脂质异常，如肥胖、高脂血症和心肌细胞内脂质水平升高与胰岛素抵抗的发展相关，胰岛素抵抗是对胰岛素的一种不正常的代谢反应。本实验室先前的研究表明，神经酰胺是饱和脂肪酸诱导的培养肌肉细胞胰岛素抵抗的必要条件和充分条件。在胰岛素抵抗的动物和人类中已经观察到神经酰胺浓度的升高，与细胞培养中看到的类似。我们假设神经酰胺是体内饱和脂肪酸诱导胰岛素抵抗的必备中间体。在本文描述的项目中，我们将在体内定量确定神经酰胺在脂肪酸诱导的胰岛素抵抗中的作用。静脉输注饱和和不饱和脂肪乳剂以及高脂肪饮食将用于促进血清游离脂肪酸的升高。我们将把肌肉和肝脏中总神经酰胺和单个神经酰胺的浓度与胰岛素敏感性联系起来。此外，我们将确定药物抑制神经酰胺合成是否会阻止游离脂肪酸诱导的胰岛素抵抗。

DESCRIPTION (provided by applicant): Lipid abnormalities, such as obesity, hyperlipidemia, and elevated intramyocellular lipid levels have been correlated with the development of insulin resistance, a subnormal metabolic response to insulin. Previous research by our laboratory indicates that ceramide is necessary and sufficient for saturated-fatty-acid-induced insulin resistance in cultured muscle cells. Elevations of ceramide concentration, similar to those seen in cell culture, have been observed in insulin resistant animals and humans. We hypothesize that ceramide is an obligate intermediate in the induction of insulin resistance by saturated fatty acids in vivo. In the project described herein, we will quantitatively determine the role of ceramide in fatty-acid-induced insulin resistance in vivo. Intravenous infusion of saturated and unsaturated lipid emulsions and administration of high fat diets will be used to promote elevations in serum free fatty acids. We will correlate concentrations of total ceramide and individual ceramide species with insulin sensitivity in muscle and liver. Additionally, we will determine whether pharmacological inhibition of ceramide synthesis will prevent the induction of insulin resistance by free fatty acids.