Bis(hinokitiolato)zinc complex ([Zn(hkt)2]) activates Akt/protein kinase B independent of insulin signal transduction

J Biol Inorg Chem. 2016 Jul;21(4):537-48. doi: 10.1007/s00775-016-1364-9. Epub 2016 Jun 1.

Abstract

Since many Zn complexes have been developed to enhance the insulin-like activity and increase the exposure and residence of Zn in the animal body, these complexes are recognized as one of the new candidates with action mechanism different from existing anti-diabetic drugs. However, the molecular mechanism by which Zn complexes exert an anti-DM effect is unknown. Therefore, we evaluated the activity of Zn complexes, especially related to the phosphorylation of insulin signaling pathway components. We focused on the insulin-like effects of the bis(hinokitiolato)zinc complex, [Zn(hkt)2], using 3T3-L1 adipocytes. [Zn(hkt)2] was taken up by cells and induced Akt phosphorylation in a time-dependent manner. Additionally, it showed inhibitory activity against PTP1B and PTEN, which are major negative regulators of insulin signaling. It did not promote the phosphorylation of IR (insulin receptor)-β or IRS (insulin receptor substrate)-1 by itself, but in combination with insulin, it enhanced the phosphorylation of IRβ. We conclude that [Zn(hkt)2] has effects on the proteins of insulin signaling pathway without insulin receptor mediation, and [Zn(hkt)2] promotes insulin function and shows the anti-DM effects. Thus, [Zn(hkt)2] may be the basis for improved DM treatments.

Keywords: Action mechanism; Diabetes mellitus; Immunoblotting; Insulin signaling; Zn complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Animals
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Insulin / metabolism*
  • Mice
  • Molecular Structure
  • Organometallic Compounds / chemical synthesis
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / pharmacology*
  • PTEN Phosphohydrolase / antagonists & inhibitors
  • PTEN Phosphohydrolase / metabolism
  • Phosphorylation / drug effects
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction* / drug effects
  • Structure-Activity Relationship

Substances

  • Insulin
  • Organometallic Compounds
  • trans-bis(hinokitiolato)copper(II)
  • Proto-Oncogene Proteins c-akt
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Ptpn1 protein, mouse
  • PTEN Phosphohydrolase
  • Pten protein, mouse