PREDOCTORAL FELLOWSHIP FOR STUDENTS WITH DISABILITIES

描述（由申请方提供）：脂质异常，如肥胖、高脂血症和肌细胞内脂质水平升高与胰岛素抵抗（对胰岛素的亚正常代谢反应）的发生相关。 本实验室先前的研究表明，神经酰胺是培养的肌肉细胞中饱和脂肪酸诱导的胰岛素抵抗的必要和充分条件。在胰岛素抵抗动物和人类中观察到神经酰胺浓度升高，与细胞培养中观察到的相似。 我们假设神经酰胺是体内饱和脂肪酸诱导胰岛素抵抗的一个强制性中间体。 在本文所述的项目中，我们将定量测定神经酰胺在体内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和给予高脂肪饲料将用于促进血清游离脂肪酸升高。 我们将把总神经酰胺和单个神经酰胺的浓度与肌肉和肝脏中的胰岛素敏感性相关联。 此外，我们将确定是否药理学抑制神经酰胺的合成将防止诱导胰岛素抵抗的游离脂肪酸。

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.