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

胰岛素与胰岛素受体（IRα）的α亚基结合，随后在细胞中发挥作用。发现几种受体的可溶性胞外域在血浆中循环。因此，我们推测糖尿病患者血浆中可能存在可溶性hIR胞外域（α亚基和部分β亚基），并通过两步纯化、免疫印迹和凝胶过滤层析鉴定了人血浆中可溶性hIR胞外域。此外，我们还建立了hIRa特异性酶联免疫吸附试验（ELISA），并测定了糖尿病（DM）患者的血浆伊拉水平。我们还在链脲佐菌素诱导的糖尿病hIR转基因小鼠中研究了这一现象。人血浆中存在可溶性hIRa，而不是完整的hIRβ或完整的hIR。2型和1型DM患者的血浆伊拉水平显著高于对照受试者（2.26 ± 0.80（2型，n=473）和2.00 ± 0.60 ng/ml（1型，n=53）vs. 1.59 ± 0.40 ng/ml（对照，n=123），p<0.001 vs.对照）。血浆伊拉）水平与血糖水平呈正相关，患者血浆中10-20%的胰岛素与hIR α结合。在体内实验中，高血糖可使hIR α水平升高，半衰期约为6 × 6 h，提示hIR α水平升高可能是比糖化血红蛋白（HbA 1c）或糖蛋白（glycobalb）更快的血糖标志物。

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.