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

¹Division of Molecular Genetics,
⁵Division of Molecular Immunology, Institute for Enzyme Research,
²Department of Pediatrics,
⁷Department of Medicine and Bioregulatory Science, Graduate School of Medicine, The University of Tokushima, Tokushima 770-8503, Japan,
³Medical & Biological Laboratories Co. Ltd., Nagoya 460-0002, Japan,
⁴Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan,
⁶Naruto Hospital, Naruto, Tokushima 772-8503, Japan,
⁸Division of Life Style Diseases, Institutes for Health Science, Tokushima Bunri University, Tokushima 770-8514, Japan

Correspondence: ebina{at}ier.tokushima-u.ac.jp

"Objectives": Insulin binds to the -subunit of the insulin receptor (IR), 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 (-subunit and a part of ß-subunit) may exist in the plasma of diabetes patients.

"Research Design and Methods": 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 hIR-specific enzyme-linked immunosorbent assay (ELISA) and measured the plasma IR levels in patients with diabetes mellitus (DM). We also investigated this phenomenon in streptozotocin-induced diabetic hIR transgenic mice.

"Results": The soluble hIR, but not intact hIRß or whole hIR, exists in human plasma. The plasma IR 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 IR level was positively correlated with the blood glucose level and 10-20% of the insulin in patient plasma bound to hIR. In the in vivo experiments using diabetic hIR transgenic mice, hyperglycemia was confirmed to increase the plasma hIR level and the half-life was estimated to be 6 h.

"Conclusion": We propose that the increased soluble IR ectodomain level appears to be a more rapid glycemic marker compared to HbA1c or glycoalbumin.

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