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

Toshiyuki Obata, Ichiro Yokota, Kazuhiro Yokoyama, Eiji Okamoto, Yoshiko Kanezaki, Yoshinori Tanaka, Hiroshi Maegawa, Kiyoshi Teshigawara, Fumiko Hirota, Tomoyuki Yuasa, Kazuhiro Kishi, Atsushi Hattori, Seiichi Hashida, Kazuhiko Masuda, Mitsuru Matsumoto, Toshio Matsumoto, Atsunori Kashiwagi, Yousuke Ebina

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE-Insulin binds to the α-subunit of the insulin receptor (IRα) 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 (α-subunit and a part of β-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 hIRα-specific enzyme-linked immunosorbent assay and measured the plasma IRα levels in patients with diabetes. We also investigated this phenomenon in streptozotocin-induced diabetic hIR transgenic mice. RESULTS-Soluble hIRα, but not intact hIRβ or whole hIR, exists in human plasma. The plasma IRα 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 IRα level was positively correlated with blood glucose level, and 10-20% of the insulin in plasma bound to hIRα. In the in vivo experiments using diabetic hIR transgenic mice, hyperglycemia was confirmed to increase the plasma hIRα level and the half-life estimated to be ∼6 h. CONCLUSIONS-We propose that the increased soluble IR ectodomain level appears to be a more rapid glycemic marker than A1C or glycoalbumin.

Original languageEnglish
Pages (from-to)2028-2035
Number of pages8
JournalDiabetes
Volume56
Issue number8
DOIs
Publication statusPublished - Aug 2007
Externally publishedYes

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Insulin Receptor
Insulin
Transgenic Mice
human INSR protein
Streptozocin
Immunoblotting
Hyperglycemia
Gel Chromatography
Half-Life
Blood Glucose
Research Design
Enzyme-Linked Immunosorbent Assay

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Obata, T., Yokota, I., Yokoyama, K., Okamoto, E., Kanezaki, Y., Tanaka, Y., ... Ebina, Y. (2007). Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes. Diabetes, 56(8), 2028-2035. https://doi.org/10.2337/db07-0394

Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes. / Obata, Toshiyuki; Yokota, Ichiro; Yokoyama, Kazuhiro; Okamoto, Eiji; Kanezaki, Yoshiko; Tanaka, Yoshinori; Maegawa, Hiroshi; Teshigawara, Kiyoshi; Hirota, Fumiko; Yuasa, Tomoyuki; Kishi, Kazuhiro; Hattori, Atsushi; Hashida, Seiichi; Masuda, Kazuhiko; Matsumoto, Mitsuru; Matsumoto, Toshio; Kashiwagi, Atsunori; Ebina, Yousuke.

In: Diabetes, Vol. 56, No. 8, 08.2007, p. 2028-2035.

Research output: Contribution to journalArticle

Obata, T, Yokota, I, Yokoyama, K, Okamoto, E, Kanezaki, Y, Tanaka, Y, Maegawa, H, Teshigawara, K, Hirota, F, Yuasa, T, Kishi, K, Hattori, A, Hashida, S, Masuda, K, Matsumoto, M, Matsumoto, T, Kashiwagi, A & Ebina, Y 2007, 'Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes', Diabetes, vol. 56, no. 8, pp. 2028-2035. https://doi.org/10.2337/db07-0394
Obata T, Yokota I, Yokoyama K, Okamoto E, Kanezaki Y, Tanaka Y et al. Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes. Diabetes. 2007 Aug;56(8):2028-2035. https://doi.org/10.2337/db07-0394
Obata, Toshiyuki ; Yokota, Ichiro ; Yokoyama, Kazuhiro ; Okamoto, Eiji ; Kanezaki, Yoshiko ; Tanaka, Yoshinori ; Maegawa, Hiroshi ; Teshigawara, Kiyoshi ; Hirota, Fumiko ; Yuasa, Tomoyuki ; Kishi, Kazuhiro ; Hattori, Atsushi ; Hashida, Seiichi ; Masuda, Kazuhiko ; Matsumoto, Mitsuru ; Matsumoto, Toshio ; Kashiwagi, Atsunori ; Ebina, Yousuke. / Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes. In: Diabetes. 2007 ; Vol. 56, No. 8. pp. 2028-2035.
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T1 - Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes

AU - Obata, Toshiyuki

AU - Yokota, Ichiro

AU - Yokoyama, Kazuhiro

AU - Okamoto, Eiji

AU - Kanezaki, Yoshiko

AU - Tanaka, Yoshinori

AU - Maegawa, Hiroshi

AU - Teshigawara, Kiyoshi

AU - Hirota, Fumiko

AU - Yuasa, Tomoyuki

AU - Kishi, Kazuhiro

AU - Hattori, Atsushi

AU - Hashida, Seiichi

AU - Masuda, Kazuhiko

AU - Matsumoto, Mitsuru

AU - Matsumoto, Toshio

AU - Kashiwagi, Atsunori

AU - Ebina, Yousuke

PY - 2007/8

Y1 - 2007/8

N2 - OBJECTIVE-Insulin binds to the α-subunit of the insulin receptor (IRα) 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 (α-subunit and a part of β-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 hIRα-specific enzyme-linked immunosorbent assay and measured the plasma IRα levels in patients with diabetes. We also investigated this phenomenon in streptozotocin-induced diabetic hIR transgenic mice. RESULTS-Soluble hIRα, but not intact hIRβ or whole hIR, exists in human plasma. The plasma IRα 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 IRα level was positively correlated with blood glucose level, and 10-20% of the insulin in plasma bound to hIRα. In the in vivo experiments using diabetic hIR transgenic mice, hyperglycemia was confirmed to increase the plasma hIRα level and the half-life estimated to be ∼6 h. CONCLUSIONS-We propose that the increased soluble IR ectodomain level appears to be a more rapid glycemic marker than A1C or glycoalbumin.

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