【作者】 刘毅；

【导师】 赵家军；

【作者基本信息】 山东大学 ， 内分泌与代谢病， 2006， 博士

【摘要】 背景： 生理剂量的胰岛素发挥不了相应的生物学效应即为胰岛素抵抗，遗传因素和环境因素均可诱导胰岛素抵抗。近年来，随着人们生活水平的提高和生活方式的改变，胰岛素抵抗和2型糖尿病发病率逐渐增高，环境因素对胰岛素抵抗的作用也引起人们更多的关注。其中，高脂饮食对胰岛素敏感性的影响是近年来的研究热点，即所谓脂毒性（lipotoxicity）。大量的流行病学资料提示：长期高脂饮食的人群胰岛素抵抗和2型糖尿病发病率明显高于正常人群；实验室资料也证实：高脂环境可以损害包括骨骼肌、肝脏和脂肪在内的多种胰岛素靶器官的胰岛素敏感性。目前认为，高脂环境是诱发胰岛素抵抗的独立危险因素之一。 高脂环境诱导的胰岛素抵抗伴有胰岛素信号传递通路多个环节表达或活性的异常：如胰岛素与受体的结合能力降低，胰岛素受体、胰岛素受体底物以及磷脂酰肌醇3激酶（PI₃K）活性下降，葡萄糖转运体4（GluT4）表达降调等。这些均被认为是高脂环境诱导胰岛素抵抗的可能机制。然而高脂环境下，上述胰岛素信号分子表达或活性改变的上游机制目前还不清楚。 AMPK（AMP-activated Potein Kinase），即AMP激活的蛋白激酶，是哺乳动物细胞能量代谢的一种重要的调节因子。AMPK最主要的生物学效应是通过感受胞浆内AMP／ATP比值的变化，调节脂肪酸的氧化代谢。除调节能量代谢外，AMPK还参与机体胰岛素敏感性调节。研究发现，AMPK基因剔除的小鼠表现出明显的胰岛素抵抗，而AMPK过表达则具有明显的胰岛素增敏效应。目前认为：AMPK是机体胰岛素敏感性的一种正调节因子，其对胰岛素敏感性的调节作用一方面与其对细胞内脂肪酸氧化代谢的调节有关，另一方面AMPK还可直接调节GluT4的表达。 新近研究发现：高糖环境诱导的胰岛素抵抗伴有AMPK活性的降调，提示更多还原

【Abstract】 Background:High-fat diet is a single risk factor leading to insulin resistance and type 2 diabetes, also named as "lipotoxocity", which is characterized by increased body weight, elevated plasma FFA levels and abnormal accumulation of fat in insulin target organs. Although both epidemlogical and experimential researches have demonstrated the effects of high-fat exposure on insulin resistance in several insulin target organs, including skeletal muscles, liver, adipocytes etc, the precise mechanism is not fully eludiated yet.To date, both in vivo and in vitro studies have demonstrated that high-fat induced insulin resistance is accompanied with impaired activity or expression of several insulin signal moleculars, such as insulin receptor, insulin receptor substrate and GluT4 etc, and this was proposed as possible contributors to high-fat induced insulin resistance. However, the upstream mechanism underlying such impaired insulin signaling caused by high-fat exposure remains unclear.AMPK, AMP-activated protein kinase, is a key regulator of intracellular fatty acid metabolism. Stresses such as exercise, hypoxia, or prolonged starvation could activate AMPK via increasing intracellular AMP/ATP ratio. Once activated, its classical effect is to phosphorylate and inactivate acetyl-CoA carboxylase (ACC), resulting in a decrease in malonyl-CoA, thus relieving inhibition of CPT1 and facilitating FFA entry into mitochondria for P-oxidation. Besides regulating fatty acid oxidation, AMPK has been proved recently as a regulator of insulin signaling. For example, it was showed that AMPK-knockout mice became more insulin resistant, while those with AMPK overexpression exhibited enhanced insulin sensitivity. Recently, it was reported that AMPK activities in cultured skeletal muscle cells could be decreased by glucose更多还原