The Role of Protein Kinase C epsilon in the Generation of Lipid-Induced Insulin Resistance in Skeletal Muscle

胰岛素通常通过增加某些组织，特别是肌肉中葡萄糖的摄取和储存来降低血糖水平。2型糖尿病的特点是这些组织对胰岛素反应不足。这种对激素敏感性的丧失被称为胰岛素抵抗，并与脂肪可获得性的增加密切相关，尽管原因尚不清楚。某些脂肪分子能够引起细胞内通路的激活，从而干扰胰岛素的正常信号传递。我们最近发现，缺乏一种被认为参与这种负面途径的酶的小鼠不太容易受到高脂肪喂养引起的胰岛素抵抗的影响。本项目的目的是研究该酶抑制胰岛素作用的机制。我们将确定正常胰岛素信号传递的步骤，该信号在脂肪供应增加时被酶激活所阻断。这将帮助我们确定从酶到胰岛素信号的途径。我们还将确定导致酶激活的特定形式的脂肪。这项工作将有助于更好地理解脂肪在胰岛素抵抗的产生中发挥作用的机制，以便将它们作为靶点，开发更有效的新疗法来治疗这种疾病，并预防其发病。

Insulin normally reduces blood sugar levels by increasing glucose uptake and storage in certain tissues, especially muscle. Type 2 diabetes is characterized by a failure of these tissues to respond adequately to insulin. This loss of sensitivity to the hormone is known as insulin resistance, and has been strongly linked to increases in the availability of fat, although the reasons for this are not clear. Certain fat molecules are able to cause the activation of pathways within cells which can interfere with the normal signalling of insulin. We have recently found that mice lacking an enzyme thought to be involved in such negative pathways are less susceptible to insulin resistance caused by high-fat feeding. The aim of this project is to investigate the mechanism by which this enzyme contributes to inhibition of insulin action. We will determine the step in normal insulin signalling which is blocked by the activation of the enzyme upon increased fat supply. This will help us to determine the pathway leading from the enzyme to insulin signalling. We will also identify the particular form of fat which leads to activation of the enzyme. This work will lead to a better understanding of the mechanisms by which fats can play a role in the generation of insulin resistance, so that they can be targeted both for the development of new and more effective treatments for the disorder and for prevention of its onset.