Tissue-Specific Difference in the Molecular Mechanisms for the Development of Acute Insulin Resistance after Injury
Tissue-Specific Difference in the Molecular Mechanisms for the Development of Acute Insulin Resistance after Injury
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DOI：
10.1210/en.2008-0742
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发表时间：
2009-01-01
期刊：
影响因子：
4.8
通讯作者：
Messina, Joseph L.
中科院分区：
文献类型：
--
作者：
Li, Li;Thompson, LaWanda H.;Messina, Joseph L.
急性胰岛素抵抗发生在损伤、出血、感染和危重疾病之后。然而，人们对这种急性胰岛素抵抗状态的发展知之甚少。在目前的研究中，我们发现骨骼肌的胰岛素抵抗发展迅速，最早的胰岛素信号缺陷出现在60分钟。然而，在出血后15分钟，肝脏中胰岛素信号的缺陷甚至可以更早地测量到。为了了解急性胰岛素抵抗的发生机制，我们研究了胰岛素受体底物(IRS)-1丝氨酸磷酸化和c-Jun n -末端激酶磷酸化/活化。这些胰岛素抵抗的标志物（和可能的贡献者）在出血后的肝脏中增加，但在骨骼肌中没有测量到。由于糖皮质激素是负责葡萄糖稳态的重要反调节激素，因此在出血前给成年大鼠使用糖皮质激素合成抑制剂美替拉酮和糖皮质激素受体拮抗剂RU486。在肝脏中，大鼠出血后胰岛素信号通路的缺陷，包括胰岛素受体和IRS-1的酪氨酸磷酸化降低，IRS-1与磷脂酰肌醇3-激酶的关联以及Akt对胰岛素的丝氨酸磷酸化均未被甲替酮或RU486预处理改变。相反，出血性胰岛素信号缺陷在骨骼肌中被显著逆转，表明肌肉中的胰岛素抵抗得到了预防。这些结果表明，出血诱导的急性胰岛素抵抗的不同机制存在于这两种组织中，并且糖皮质激素参与了出血后骨骼肌而不是肝脏中胰岛素抵抗的快速发展。（内分泌学150:24-32,2009）
Acute insulin resistance occurs after injury, hemorrhage, infection, and critical illness. However, little is known about the development of this acute insulin-resistant state. In the current study, we found that insulin resistance develops rapidly in skeletal muscle, with the earliest insulin signaling defects at 60 min. However, defects in insulin signaling were measurable even earlier in liver, by as soon as 15 min after hemorrhage. To begin to understand the mechanisms for the development of acute insulin resistance, serine phosphorylation of insulin receptor substrate (IRS)-1 and c-Jun N-terminal kinase phosphorylation/activation was investigated. These markers (and possible contributors) of insulin resistance were increased in the liver after hemorrhage but not measurable in skeletal muscle. Because glucocorticoids are important counterregulatory hormones responsible for glucose homeostasis, a glucocorticoid synthesis inhibitor, metyrapone, and a glucocorticoid receptor antagonist, RU486, were administered to adult rats prior to hemorrhage. In the liver, the defects of insulin signaling after hemorrhage, including reduced tyrosine phosphorylation of the insulin receptor and IRS-1, association between IRS-1 and phosphatidylinositol 3-kinase and serine phosphorylation of Akt in response to insulin were not altered by pretreatment of rats with metyrapone or RU486. In contrast, hemorrhage-induced defects in insulin signaling were dramatically reversed in skeletal muscle, indicating a prevention of insulin resistance in muscle. These results suggest that distinct mechanisms for hemorrhage-induced acute insulin resistance are present in these two tissues and that glucocorticoids are involved in the rapid development of insulin resistance in skeletal muscle, but not in the liver, after hemorrhage. (Endocrinology 150: 24-32, 2009)