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，随后在细胞内发挥作用。几种受体的可溶性胞外区在血浆中循环。因此，我们推测糖尿病患者血浆中可能存在可溶性人IR胞外结构域(α-亚基和部分β-亚基)。此外，我们还建立了HIRA特异性的酶联免疫吸附试验(EL ISA)，并测定了糖尿病(DM)患者血浆IRA水平。在链脲佐菌素诱导的糖尿病hir转基因小鼠中，我们也研究了这一现象。人血浆中存在可溶性hirA，但不存在完整的hirβ或完整的hir。2型糖尿病患者和1型糖尿病患者血浆IRA水平分别为2.2 6±0.80(n=4 73)和2.0 0±0.6 0 ng/m l(n=5 3)，明显高于对照组的1.5 9±0.4 0 ng/m l(P<0.0 1)，P<0.0 1。血浆IRA水平与血糖水平、HIRA结合患者血浆胰岛素的10-20%呈正相关。在利用糖尿病hir转基因小鼠进行的体内实验中，证实高血糖会增加血浆Hira水平，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.