Molecular mechanism of antidiabetic zinc-allixin complexes: regulations of glucose utilization and lipid metabolism.
We previously reported new zinc complexes of allixin [bis(allixinato)zinc] and its derivative bis(thioallixin-N-methyl)zinc that demonstrated excellent antidiabetic activity in type 2 diabetic mellitus KKA(y) mice. However, the molecular mechanism of these complexes is not fully understood. Thus, we attempted to reveal the intracellular mechanism of these complexes in 3T3-L1 adipocytes. Both zinc complexes induced Akt/protein kinase B (Akt/PKB) phosphorylation. The phosphorylation of Akt/PKB enhanced glucose transporter 4 translocation to the plasma membrane; this in turn enhanced the glucose utilization in a dose- and time-dependent manner. Glucose utilization by the complexes depended on the intracellular zinc concentration. Moreover, zinc complexes suppressed the cyclic AMP dependent protein kinase mediated phosphorylation of hormone-sensitive lipase (HSL), leading to the inhibition of free fatty acid release from the 3T3-L1 adipocytes. Such responses were inhibited by wortmannin, suggesting that the suppression of HSL by zinc complexes was dependent in the phosphoinositide 3-kinase-Akt/PKB signaling cascade. On the basis of these results, we proposed that both zinc complexes activated the Akt/PKB-mediated insulin-signaling pathway and improved both glucose utilization and lipid metabolism.
Nakayama
Akihiro
A
Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan.
Hiromura
Makoto
M
Adachi
Yusuke
Y
Sakurai
Hiromu
H
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D051058:Oncogene Protein v-akt / Q000502:physiology*; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D002787:Sterol Esterase / Q000378:metabolism; D014178:Translocation, Genetic; D000077191:Wortmannin
D000730:Androstadienes; D005230:Fatty Acids, Nonesterified; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D009942:Organometallic Compounds; C499174:bis(allixinato)zinc; C531897:bis(thioallixin-N-methyl)zinc(II); D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D051057:Proto-Oncogene Proteins c-akt; D002787:Sterol Esterase; D005947:Glucose; D000077191:Wortmannin