Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes

糖尿病患者血浆中可溶性胰岛素受体胞外域升高

• 批准号: 17590269
• 负责人: OBATA Toshiyuki
• 金额: $ 2.3万
• 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 (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590269/
• 关键词: Soluble Insulin Receptor; diabetes; glycemic marker; シグナル伝達; 血中可溶性インスリン受容体; 生理活性; インスリン受容体

Insulin binds to the a-subunit of the insulin receptor (IRα), and subsequently exerts its effects in the cells. The soluble ectodomains of several receptors were found to circulate in the plasma. Therefore, we hypothesized that soluble human IR ectodomain (α-subunit and a part of β-subunit) may exist in the plasma of diabetes patients.We identified soluble hIR ectodomain in human plasma by a two-step purification followed by immunoblotting and by a gel-filtration chromatography. Furthermore, we established a hIRa-specific enzyme-linked immunosorbent assay (ELISA) and measured the plasma IRa levels in patients with diabetes mellitus (DM). We also investigated this phenomenon in streptozotocin-induced diabetic hIR transgenic mice.The soluble hIRa, but not intact hIRβ or whole hIR, exists in human plasma. The plasma IRa levels were significantly higher in patients with type 2 and type 1 DM than in control subjects (2.26 ± 0.80 (type 2, n=473) and 2.00 ± 0.60 ng/ml (type 1, n=53) vs. 1.59 ± 0.40 ng/ml (control, n=123), p<0.001 vs. the control). The plasma IRa level was positively correlated with the blood glucose level and 10-20% of the insulin in patient plasma bound to hIRa. In the in vivo experiments using diabetic hIR transgenic mice, hyperglycemia was confirmed to increase the plasma hIRa level and the half-life was estimated to be6 〜6h.We propose that the increased hIRa level appeared to be more rapid glycemic marker compared to HbA1c or glycoalbumin.

胰岛素与胰岛素受体（IRα）的a亚基结合，随后在细胞中发挥其作用。发现几种受体的可溶性外结构域在血浆中循环。因此，我们推测糖尿病患者血浆中可能存在可溶性人IR外结构域（α-亚基和部分β-亚基）。我们通过免疫印迹和凝胶过滤层析两步纯化，鉴定了人血浆中的可溶性hIR外畴。此外，我们建立了hira特异性酶联免疫吸附试验（ELISA），并测量了糖尿病（DM）患者的血浆IRa水平。我们也在链脲佐菌素诱导的糖尿病hIR转基因小鼠中研究了这种现象。人血浆中存在可溶性hIR，但不存在完整的hIRβ或整个hIR。2型和1型糖尿病患者血浆IRa水平显著高于对照组(2.26±0.80（2型，n=473）和2.00±0.60 ng/ml(1型，n=53)，分别高于1.59±0.40 ng/ml（对照组，n=123）， p<0.001。血浆IRa水平与血糖水平及患者血浆中10-20%与hIRa结合的胰岛素呈正相关。在糖尿病hIR转基因小鼠体内实验中，证实高血糖使血浆hIRa水平升高，半衰期估计为6 ~ 6h。我们认为，与HbA1c或糖蛋白相比，hIRa水平升高似乎是更快的血糖指标。

项目成果

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

Angiotensin II inhibits insulin-induced actin stress fiber formation and elucose uptake via ERK1/2

血管紧张素 II 通过 ERK1/2 抑制胰岛素诱导的肌动蛋白应激纤维形成和葡萄糖摄取

• 发表时间: 2007
• 期刊: The Journal of Medical Investigation 54-(1,2)
• 作者: Adachi M;Sakamoto H;Kawamura R;Wang W;Imai K;Shinomura Y.;Nazari H.
• 通讯作者: Nazari H.

糖尿病の治療薬のスクリーニング方法

糖尿病治疗药物的筛选方法

• 发表时间: 2005

APS-mediated ubiquitination of the insulin receptor enhances its internalization, but does not induce its degradation.

• DOI: 10.1507/endocrj.k06-056
• 发表时间: 2007-02
• 期刊: Endocrine journal
• 影响因子: 2
• 作者: K. Kishi;K. Mawatari;Kikuko Sakai-Wakamatsu;T. Yuasa;Miao Wang;Makoto Ogura-Sawa;Y. Nakaya;S. Hatakeyama;Y. Ebina

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