Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance
Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance
复制标题
DOI：
10.1073/pnas.121164498
复制
发表时间：
2001-06-19
影响因子：
11.1
通讯作者：
Shulman, GI
中科院分区：
文献类型：
--
作者：
Kim, JK;Fillmore, JJ;Shulman, GI
骨骼肌和肝脏的胰岛素抵抗可能在2型糖尿病的发生发展中起主要作用，胰岛素抵抗的发生机制可能与脂肪代谢的改变有关。在2小时的高胰岛素-正常血糖钳夹中，研究了肌肉和肝脏特异性脂蛋白脂酶过表达的转基因小鼠，以确定组织特异性脂肪增加对胰岛素作用和信号转导的影响。肌肉脂蛋白脂肪酶小鼠的肌肉甘油三酯含量增加了3倍，并且出现了胰岛素抵抗，这是因为骨骼肌对胰岛素刺激的葡萄糖摄取减少，胰岛素受体底物L相关的磷脂酰肌醇3-激酶活性的胰岛素激活。相比之下，肝脂蛋白脂肪酶小鼠的肝脏甘油三酯含量增加了2倍，由于胰岛素抑制内源性葡萄糖产生的能力受损，以及胰岛素受体底物-2相关磷脂酰肌醇3-激酶活性的缺陷，小鼠出现了胰岛素抵抗。这些胰岛素作用和信号的缺陷与细胞内脂肪酸衍生代谢物的增加有关(即。二酰甘油、脂肪酰辅酶A、神经酰胺)。我们的发现表明，细胞内脂肪酸衍生代谢物的积累与胰岛素抵抗之间存在直接的因果关系，这种关系是通过胰岛素信号通路的改变来介导的，而不是依赖于循环中的脂肪细胞衍生激素。
Insulin resistance in skeletal muscle and liver may play a primary role in the development of type 2 diabetes mellitus, and the mechanism by which insulin resistance occurs may be related to alterations in fat metabolism. Transgenic mice with muscle- and liver-specific overexpression of lipoprotein lipase were studied during a 2-h hyperinsulinemic-euglycemic clamp to determine the effect of tissue-specific increase in fat on insulin action and signaling. Muscle-lipoprotein lipase mice had a 3-fold increase in muscle triglyceride content and were insulin resistant because of decreases in insulin-stimulated glucose uptake in skeletal muscle and insulin activation of insulin receptor substrate-l-associated phosphatidylinositol 3-kinase activity. In contrast, liver-lipoprotein lipase mice had a 2-fold increase in liver triglyceride content and were insulin resistant because of impaired ability of insulin to suppress endogenous glucose production associated with defects in insulin activation of insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity. These defects in insulin action and signaling were associated with increases in intracellular fatty acid-derived metabolites (i.e.. diacylglycerol, fatty acyl CoA, ceramides). Our findings suggest a direct and causative relationship between the accumulation of intracellular fatty acid-derived metabolites and insulin resistance mediated via alterations in the insulin signaling pathway, independent of circulating adipocyte-derived hormones.