Cellular Mechanism of Zinc-Hinokitiol Complexes in Diabetes Mellitus

Zinc complexes exhibit high insulin-like and antidiabetic activities in animals with type 2 diabetes mellitus (DM). However, molecular mechanisms underlying these activities have not yet been determined. In this study, we investigated activation of the insulin signaling pathway by Zn in 3T3-L1 adipocytes using di(hinokitiolato)zinc complex (hinokitiol: 2-hydroxy-4-isopropylcyclohepta-2,4,6-trienone, [Zn(hnk)(2)]), which exhibits antidiabetic effect in animals with type 2 DM. Our results show that [Zn(hnk)(2)] strongly induced Akt/protein kinase B (Akt/PKB) phosphorylation, and optimal phosphorylation was achieved at a concentration of 50 mu M. The [Zn(hnk)(2)]-induced Akt/PKB phosphorylation was almost completely inhibited by wortmannin, whereas [Zn(hnk)(2)]-induced phosphorylation of glycogen synthase kinase-3 beta (GSK3 beta) was partially inhibited by wortmannin. Further, we examined cellular Zn uptake by [Zn(hnk)(2)] stimulation and evaluated cellular glucose uptake at the same time point. The intracellular Zn concentration incubated with [Zn(hnk)(2)] was approximately 4.7-fold higher than that in the control cells. Moreover, the glucose uptake of [Zn(hnk)(2)]-treated adipocytes was 3.7-fold higher than that of the control adipocytes. These results suggest that [Zn(hnk)(2)] was able to translocate glucose transporter 4 (GLUT4) protein to the plasma membrane. Thus, we propose that [Zn(hnk)(2)] produces the antidiabetic effect by inducing insulin signaling pathways and glucose uptake.