Journal
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY
Volume 21, Issue 4, Pages 537-548Publisher
SPRINGER
DOI: 10.1007/s00775-016-1364-9
Keywords
Zn complex; Diabetes mellitus; Insulin signaling; Action mechanism; Immunoblotting
Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) Supported Program for the Strategic Research Foundation at Private Universities [S1201008]
- JSPS KAKENHI [25460048, 26460636]
- Grants-in-Aid for Scientific Research [25460048] Funding Source: KAKEN
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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)-beta or IRS (insulin receptor substrate)-1 by itself, but in combination with insulin, it enhanced the phosphorylation of IR beta. 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.
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