Pathological mechanism of sequential cleavage model of insulin receptor

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K09391
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: The University of Tokushima
• Principal Investigator: YUASA Tomoyuki 徳島大学, 大学院医歯薬学研究部(医学系), 特任准教授 (50304556)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 可溶性インスリン受容体 / インスリン抵抗性 / 糖尿病

Outline of Final Research Achievements

Soluble insulin receptor (sIR), the ectodomain of IR, was detected in human plasma and its concentration paralleled that of blood glucose. We have previously developed an in vitro model using HepG2 liver-derived cells, which mimics changes in sIR levels in plasma from patients with diabetes. Using the in vitro model, we determined that calpain 2, which is secreted into the extracellular space associated with exosomes, cleaved the ectodomain of IRβ subunit, which in turn promoted the intramembrane cleavage of IRβ subunit by γ-secretase. IR cleavage impaired insulin signalling, and the inhibition of IR cleavage restored it. The antidiabetic drug, metformin, prevented IR cleavage. In patients with type 2 diabetes, plasma sIR levels inversely correlated with insulin sensitivity. Furthermore, female hormone was also shown to promote insulin receptor cleavage.

Free Research Field

生化学　分子生物学　糖尿病学