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

Objective-Insulin binds to the alpha-subunit of the insulin receptor (IR alpha) and subsequently exerts its effects in the cells. The soluble ectodomains of several receptors have been found to circulate in the plasma. Therefore, we hypothesized that soluble human insulin receptor (hIR) ectodomain (alpha-subunit and a part of beta-subunit) may exist in the plasma of diabetic patients. Research design and methods-We identified soluble hIR ectodomain in human plasma by a two-step purification followed by immunoblotting and gel-filtration chromatography. Furthermore, we established an hIR alpha-specific enzyme-linked immunosorbent assay and measured the plasma IR alpha levels in patients with diabetes. We also investigated this phenomenon in streptozotocin-induced diabetic hIR transgenic mice. Results-Soluble hIR alpha, but not intact hIR beta or whole hIR, exists in human plasma. The plasma IR alpha levels were significantly higher in type 1 (2.00 +/- 0.60 ng/ml; n = 53) and type 2 (2.26 +/- 0.80; n = 473) diabetic patients than in control subjects (1.59 +/- 0.40 ng/ml; n = 123 (P < 0.001 vs. control). Plasma IR alpha level was positively correlated with blood glucose level, and 10-20% of the insulin in plasma bound to hIR alpha. In the in vivo experiments using diabetic hIR transgenic mice, hyperglycemia was confirmed to increase the plasma hIR alpha level and the half-life estimated to similar to 6 h. Conclusions-We propose that the increased soluble IR ectodomain level appears to be a more rapid glycemic marker than A1C or glycoalbumin.