REGULATION OF INSULIN-RECEPTOR SUBSTRATE-1 IN LIVER AND MUSCLE OF ANIMAL-MODELS OF INSULIN RESISTANCE
REGULATION OF INSULIN-RECEPTOR SUBSTRATE-1 IN LIVER AND MUSCLE OF ANIMAL-MODELS OF INSULIN RESISTANCE
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DOI：
10.1172/jci116060
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发表时间：
1992-11-01
影响因子：
15.9
通讯作者：
KAHN, CR
中科院分区：
文献类型：
--
作者：
SAAD, MJA;ARAKI, E;KAHN, CR
在大多数细胞类型中，胰岛素快速刺激约185 kD的蛋白质的酪氨酸磷酸化。这种蛋白质，称为胰岛素受体底物-1（IRS-1），基于对胰岛素受体突变体的研究，已经涉及胰岛素信号传递。在本研究中，我们已经在两种胰岛素抵抗大鼠模型中检测了体内胰岛素刺激后肝脏和肌肉中IRS-1的水平以及胰岛素受体和IRS-1的磷酸化状态，如前所述，在禁食和链脲佐菌素诱导的（STZ）糖尿病大鼠的肌肉中，胰岛素结合增加，胰岛素刺激的受体磷酸化平行增加。在这两种模型中，肝脏中的总体受体磷酸化也有适度增加，但当结合增加标准化时，STZ糖尿病的肝脏和肌肉以及禁食72 h大鼠的肝脏中的受体磷酸化降低。在高胰岛素血症的ob/ob小鼠中，肝脏和肌肉中的胰岛素结合和受体磷酸化减少。胰岛素刺激后IRS-1的酪氨酰磷酸化反应了低胰岛素血症动物（禁食和STZ糖尿病）肝脏和肌肉中受体磷酸化的放大，增加了两倍，并显示出ob/ob小鼠肝脏和肌肉中的显著减少（约50%）。相比之下，IRS-1蛋白水平显示出组织特异性调节，在胰岛素抵抗的低胰岛素血症状态下，肌肉中的IRS-1蛋白水平降低，肝脏中的IRS-1蛋白水平升高，而在高胰岛素血症ob/ob小鼠中，肝脏中的IRS-1蛋白水平降低。这些数据表明：（a）IRS-1蛋白水平在肝脏和肌肉中受到不同的调节;（B）胰岛素水平可能在IRS-1的这种不同调节中起作用;（c）IRS-1磷酸化比IRS-1蛋白水平更依赖于胰岛素受体激酶活性;（d）肝脏和肌肉中IRS-1磷酸化的减少可能在胰岛素抵抗状态中起作用，特别是在ob/ob小鼠中。
Insulin rapidly stimulates tyrosine phosphorylation of a protein of approximately 185 kD in most cell types. This protein, termed insulin receptor substrate-1 (IRS-1), has been implicated in insulin signal transmission based on studies with insulin receptor mutants. In the present study we have examined the levels of IRS-1 and the phosphorylation state of insulin receptor and IRS-1 in liver and muscle after insulin stimulation in vivo in two rat models of insulin resistance, i.e., insulinopenic diabetes and fasting, and a mouse model of non-insulin-dependent diabetes mellitus (ob/ob) by immunoblotting with anti-peptide antibodies to IRS-1 and anti-phosphotyrosine antibodies.As previously described, there was an increase in insulin binding and a parallel increase in insulin-stimulated receptor phosphorylation in muscle of fasting and streptozotocin-induced (STZ) diabetic rats. There was also a modest increase in overall receptor phosphorylation in liver in these two models, but when normalized for the increase in binding, receptor phosphorylation was decreased, in liver and muscle of STZ diabetes and in liver of 72 h fasted rats. In the hyperinsulinemic ob/ob mouse there was a decrease in insulin binding and receptor phosphorylation in both liver and muscle. The tyrosyl phosphorylation of IRS-1 after insulin stimulation reflected an amplification of the receptor phosphorylation in liver and muscle of hypoinsulinemic animals (fasting and STZ diabetes) with a twofold increase, and showed a significant reduction (approximately 50%) in liver and muscle of ob/ob mouse. By contrast, the levels of IRS-1 protein showed a tissue specific regulation with a decreased level in muscle and an increased level in liver in hypoinsulinemic states of insulin resistance, and decreased levels in liver in the hyperinsulinemic ob/ob mouse. These data indicate that: (a) IRS-1 protein levels are differentially regulated in liver and muscle; (b) insulin levels may play a role in this differential regulation of IRS-1; (c) IRS-1 phosphorylation depends more on insulin receptor kinase activity than IRS-1 protein levels; and (d) reduced IRS-1 phosphorylation in liver and muscle may play a role in insulin-resistant states, especially of the ob/ob mice.