Dose calpain cleave insulin receptor, leading to the development of diabetes ?

• Project/Area Number: 25870483
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics; Pathological medical chemistry
• Research Institution: Yamaguchi University
• Principal Investigator: SHIINOKI Kikuko 山口大学, 医学部, 学術研究員 (60609692)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: インスリン受容体切断 / インスリン抵抗性 / 可溶性インスリン受容体

Outline of Final Research Achievements

Soluble insulin receptor (sIR), the ectodomain of insulin receptor (IR), is detected in human plasma, and its concentration parallels that of blood glucose in patients with diabetes. The present study demonstrated cleavage of IR in HepG2 cells treated with high glucose, and O-linked N-acetylglucosamine modification was involved in high-glucose-induced IR cleavage. Additionally, this study showed ectodomain shedding of IR is dependent on the presence of calcium-ion, raised the possibility that calpain 2, a calcium-dependent protease, is a cleavage enzyme of IR. This model also demonstrated that IR cleavage is partially responsible for the impaired insulin signaling induced by high glucose. These findings suggests that cleavage of IR is a possible component of insulin signaling in cells, and may offer considerable insight into insulin resistance-related disease.

Research Products

• [Journal Article] Development of in vitro model of insulin receptor cleavage induced by high glucose in HepG2 cells (2014)
  • Author(s): ①Yuasa T, Amo K, Ishikura S, Nagaya H, Uchiyama K, Hashida S, Ebina Y
  • Journal Title: Biochem Biophys Res Commun Volume: 445(1) Issue: 1 Pages: 236-43
  • DOI: 10.1016/j.bbrc.2014.01.187
  • Peer Reviewed
• [Journal Article] Dietary combination of sucrose and linoleic acid causes skeletal muscle metabolic abnormalities in Zucker fatty rats through specific modification of fatty acid composition (2014)
  • Author(s): Hirokazu Ohminami, Kikuko Amo, Yutaka Taketani, Kazusa Sato, Makiko Fukaya, Takashi Uebanso, Hidekazu Arai, Megumi Koganei, Hajime Sasaki, Hisami Yamanaka-Okumura, Hironori Yamamoto, Eiji Takeda
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 55 Issue: 1 Pages: 15-25
  • DOI: 10.3164/jcbn.14-11
  • NAID: 130004466759
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Presentation] Wfs1-deficiency causes beta-cell dedifferentiation associated with enhanced ER stress and oxidative stress, independently of hyperglycemia (2015)
  • Author(s): Kikuko Shiinoki, Katsuya Tanabe, Masayuki Hatanaka, Yasuharu Ohta, Yukio Tanizawa
  • Organizer: American Diabetes Association 75th Scientific Sessions
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2015-06-05 – 2015-06-09
• [Presentation] WFS1欠損膵島における膵β細胞脱分化機構の解析 (2015)
  • Author(s): 椎木幾久子、田部勝也、幡中雅行、永尾優子、太田康晴、谷澤幸生
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 海峡メッセ下関（山口県）
  • Year and Date: 2015-05-21 – 2015-05-24
• [Presentation] GLP-1受容体作動薬はWfs1欠損マウスにおけるインスリン分泌障害を改善する (2014)
  • Author(s): 椎木幾久子、田部勝也、近藤学、永尾優子、秋山優、太田康晴、谷澤幸生
  • Organizer: 第64回日本体質医学会総会
  • Place of Presentation: 中央電気倶楽部（大阪府）
  • Year and Date: 2014-09-06 – 2014-09-07
• [Presentation] 膵島炎症に対するn-3 PUFAの抑制効果とその発現機構の解明 (2014)
  • Author(s): 椎木幾久子、田部勝也、永尾優子、秋山優、太田康晴、谷澤幸生
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪国際会議場（大阪府）
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] Role of GSK3 in the development of beta cell failure (2014)
  • Author(s): Katsuya Tanabe, Yuko Nagao, Kikuko Amo, Permutt MA, Yukio Tanizawa
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪国際会議場（大阪府）
  • Year and Date: 2014-05-22 – 2014-05-24
  • Invited