Identification of a Small Molecular Insulin Receptor Agonist With Potent Antidiabetes Activity

  1. Keqiang Ye1
  1. 1Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA
  2. 2Departments of Chemistry and Biology, Center for Diagnostics and Therapeutics (CDT), Georgia State University, Atlanta, GA
  3. 3National Center for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
  4. 4Institute of Pharmacy, Henan University, Kaifeng, China
  5. 5Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL
  6. 6Department of Biochemistry, Emory University School of Medicine, Atlanta, GA
  1. Corresponding author: Chi Bun Chan, chibun-chan{at}, or Keqiang Ye, kye{at}


Insulin replacement therapy is a widely adopted treatment for all patients with type 1 diabetes and some with type 2 diabetes. However, injection of insulin has suffered from problems such as tissue irritation, abscesses, discomfort, and inconvenience. The use of orally bioactive insulin mimetics thus represents an ideal treatment alternative. Here we show that a chaetochromin derivative (4548-G05) acts as a new nonpeptidyl insulin mimetic. 4548-G05 selectively activates an insulin receptor (IR) but not insulin-like growth factor receptor-I or other receptor tyrosine kinases. Through binding to the extracellular domain of the IR, 4548-G05 induces activation of the receptor and initiates the downstream Akt and extracellular signal–related kinase pathways to trigger glucose uptake in C2C12 myotubes. Moreover, it displays a potent blood glucose-lowering effect when administrated orally in normal, type 1 diabetic, and type 2 diabetic mice models. Therefore, 4548-G05 may represent a novel pharmacological agent for antidiabetes drug development.


  • Received February 27, 2013.
  • Accepted December 19, 2013.

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