Essential role of insulin and insulin-like growth factor 1 receptor signaling in cardiac development and function
Essential role of insulin and insulin-like growth factor 1 receptor signaling in cardiac development and function
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DOI：
10.1128/mcb.01110-06
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发表时间：
2007-03-01
影响因子：
5.3
通讯作者：
Kahn, C. Ronald
中科院分区：
文献类型：
--
作者：
Laustsen, Palle G.;Russell, Steven J.;Kahn, C. Ronald
心血管疾病是2型糖尿病患者死亡的主要原因，即使没有糖尿病，也与胰岛素抵抗有关。在这里，我们表明，在心脏和骨骼肌中胰岛素受体和胰岛素样生长因子1（IGF-1）受体联合缺乏的小鼠发生早发性扩张型心肌病，并在生命的第一个月内死于心力衰竭，尽管有正常的葡萄糖稳态。缺乏胰岛素受体的小鼠在6个月时表现出心脏功能受损，缺乏胰岛素受体加上一个Igf 1 r等位基因的小鼠死亡率略有增加。相比之下，缺乏IGF-1受体或IGF-1受体加上一个Ir等位基因的小鼠看起来正常。基因表达的形态学表征和寡核苷酸阵列分析表明，在这些生理缺陷的发展之前，胰岛素和IGF-1受体联合缺乏的小鼠具有电子传递链和线粒体脂肪酸β-氧化途径的编码组分的基因的协调下调以及收缩蛋白的表达改变。因此，虽然肌肉中的胰岛素受体和IGF-1受体对于生命第一个月期间的葡萄糖稳态都不是关键的，但来自这些受体的信号传导，特别是胰岛素受体，是正常心脏代谢和功能所必需的。
Cardiovascular disease is the leading cause of death in people with type 2 diabetes and is linked to insulin resistance even in the absence of diabetes. Here we show that mice with combined deficiency of the insulin receptor and insulin-like growth factor 1 (IGF-1) receptor in cardiac and skeletal muscle develop early-onset dilated cardiomyopathy and die from heart failure within the first month of life despite having a normal glucose homeostasis. Mice lacking the insulin receptor show impaired cardiac performance at 6 months, and mice lacking the insulin receptor plus one Igf1r allele have slightly increased mortality. By contrast, mice lacking the IGF-1 receptor or the IGF-1 receptor plus one Ir allele appear normal. Morphological characterization and oligonucleotide array analysis of gene expression demonstrate that prior to development of these physiological defects, mice with combined deficiency of both insulin and IGF-1 receptors have a coordinated down-regulation of genes encoding components of the electron transport chain and mitochondrial fatty acid beta-oxidation pathways and altered expression of contractile proteins. Thus, while neither the insulin receptor nor IGF-1 receptor in muscle is critical for glucose homeostasis during the first month of life, signaling from these receptors, particularly the insulin receptor, is required for normal cardiac metabolism and function.