Molecular mechanisms of insulin signal transduction and diabetes mellitus

我们发现糖尿病(DM)患者血清胰岛素受体胞外区(IR-α)水平升高，提示高血糖导致初发1型DM患者血清IR-α升高，部分IR-α结合胰岛素。此外，我们发现IRα的释放在糖尿病动物模型中是以葡萄糖浓度依赖的方式被证实的。由于我们以前已经证明在小鼠体内注射HIRα会刺激血糖的升高，我们提出糖尿病患者中增加的IRα可能通过隔离血浆胰岛素而参与血糖控制的恶化，作为葡萄糖毒性的因素之一。APS是一种具有Pleckstrin同源和Src同源2结构域的酪氨酸激酶适配蛋白，在胰岛素刺激下被胰岛素受体激酶快速强烈地酪氨酸磷酸化。我们之前已经证明，APS基因敲除的小鼠增加了脂肪组织上的胰岛素反应。然而，到目前为止，APS在胰岛素信号转导中的作用一直存在争议。在这里，我们报告了APS增强了IR的配体依赖的多泛素化诱导的IR内化的增强，但不影响IR的降解。这一发现显示了APS在胰岛素信号传递中的多效性功能之一。

We have shown that serum levels of insulin receptor ectodomain (IRα) are elevated in patients with diabetes mellitus (DM) and shown that the hyperglycemia induced the increase of serum hIRα in newly onset of type 1 DM patients, and a part of IRα bound insulin. Furthermore, we show that the release of IRα is confirmed by diabetic animal model in a glucose concentration-dependent manner. Since we have previously shown that injection of hIRα in mice stimulates an increase in plasma glucose, we are proposing that the increased IRα in patients with DM may take part in the deterioration of glycemic control by sequestering plasma insulin, as one of the factors in glucose toxicity.APS, a tyrosine kinase adaptor protein with pleckstrin homology and Src homology 2 domains, is rapidly and strongly tyrosine-phosphorylated by insulin receptor kinase upon insulin stimulation. We have previously shown that APS knockout mice have increased insulin-response on adipose tissues. However, the function of APS in insulin signaling has so far been controversial. Here, we report that APS enhanced ligand-dependent multi-ubiquitination of the IR induced enhancement of the IR internalization, but did not affect the IR degradation. This finding shows one of the pleiotropic functions of APS in insulin signaling.