Molecular mechanisms of insulin signal transduction and diabetes mellitus

胰岛素信号转导与糖尿病的分子机制

• 批准号: 16390097
• 负责人: EBINA Yousuke
• 金额: $ 9.54万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390097/
• 关键词: insulin receptor; signal transductor; diabetes; APS; ubiquitination; internalization; 血中遊離インスリン受容体; 糖毒性

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.

我们发现糖尿病（DM）患者血清中胰岛素受体外结构域（IRα）水平升高，高血糖导致新发1型DM患者血清中hIRα水平升高，部分IRα结合胰岛素水平升高。此外，我们发现糖尿病动物模型以葡萄糖浓度依赖的方式证实了IRα的释放。由于我们之前的研究表明，在小鼠中注射IRα会刺激血浆葡萄糖的增加，我们提出糖尿病患者中升高的IRα可能通过隔离血浆胰岛素参与血糖控制的恶化，这是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衔接蛋白，在胰岛素刺激下被胰岛素受体激酶迅速而强烈地酪氨酸磷酸化。我们之前已经证明，APS基因敲除小鼠对脂肪组织的胰岛素反应增加。然而，到目前为止，APS在胰岛素信号传导中的作用一直存在争议。在这里，我们报道了APS增强了配体依赖的IR多泛素化诱导的IR内化增强，但不影响IR降解。这一发现显示了APS在胰岛素信号传导中的多效性功能之一。

项目成果

Platelet-derived growth factor stimulates glucose transport in skeletal muscles of transgenic mice specifically expressing PDGF receptor in the muscle, but does not affect blood glucose levels.

血小板衍生生长因子刺激肌肉中特异性表达 PDGF 受体的转基因小鼠骨骼肌中的葡萄糖转运，但不影响血糖水平。

• 发表时间: 2004
• 期刊: Diabetes. 53
• 作者: Tomoyuki Yuasa.;Kazuhiro Kishi.;Yousuke Ebina.;et al.
• 通讯作者: et al.

Functional analysis of PIK3CA gene mutations in human colorectal cancer

• DOI: 10.1158/0008-5472.can-04-4114
• 发表时间: 2005-06-01
• 期刊: CANCER RESEARCH
• 影响因子: 11.2
• 作者: Ikenoue, T;Kanai, F;Omata, M
• 通讯作者: Omata, M

KATP Channel Knockout Mice with transgenic Mice Expressing a Dominant-Negative Form of Human Insulin receptor have Glucose Intolerance but not Diabetes.

KATP 通道敲除小鼠与表达显性阴性形式人胰岛素受体的转基因小鼠具有葡萄糖不耐症，但没有糖尿病。

• 发表时间: 2004
• 期刊: Endocrine J. 51・2
• 作者: Yoshiko Kanezaki,;Kazuhiro Kishi;Yousuke Ebina et al.
• 通讯作者: Yousuke Ebina et al.

ERK1/2 activation by angiotensin II inhibits insulin-induced glucose uptake in vascular smooth muscle cells

• DOI: 10.1016/j.yexcr.2005.04.028
• 发表时间: 2005-08-15
• 期刊: EXPERIMENTAL CELL RESEARCH
• 影响因子: 3.7
• 作者: Izawa, Y;Yoshizumi, M;Tamaki, T
• 通讯作者: Tamaki, T

Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system

• DOI: 10.1016/j.cmet.2005.11.015
• 发表时间: 2006-01-01
• 期刊: CELL METABOLISM
• 影响因子: 29
• 作者: Xu, E;Kumar, M;Wang, QH
• 通讯作者: Wang, QH