title: Bis(hinokitiolato)zinc complex ([Zn(hkt)2]) activates Akt/protein kinase B independent of insulin signal transduction.
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.
authors.affiliation: Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Naito
authors.affiliation: Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan. y-yoshikawa@yg.kobe-wu.ac.jp.|Department of Health, Sports, and Nutrition, Faculty of Health and Welfare, Kobe Women's University, 4-7-2 Minatojima-nakamachi, Chuo-ku, Kobe, 650-0046, Japan. y-yoshikawa@yg.kobe-wu.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshikawa
authors.affiliation: Department of Physical Chemistry, Graduate School of Clinical Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama, 703-8516, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan. yasui@mb.kyoto-phu.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasui
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D007328:Insulin; D009942:Organometallic Compounds; C544642:trans-bis(hinokitiolato)copper(II); D051057:Proto-Oncogene Proteins c-akt; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Action mechanism; Diabetes mellitus; Immunoblotting; Insulin signaling; Zn complex