Since the finding of insulin-mimetic effect of Zn(II) ion, several insulin-mimetic Zn(II) complexes have been proposed. Previous studies reported an extremely high insulin-mimetic activity of Zn(II) complex with maltol (Zn(ma)2) in in vitro and in vivo evaluations. To develop more effective insulin-mimetic Zn(II) complexes than Zn(ma)2, we examined the structure-activity relationships for the Zn(ma)2 and its related complexes. From the results, a new Zn(II) complex (Zn(alx)2) with allixin, isolated from garlic as a bioactive product induced by continuous environmental stress, was found to exhibit the highest in vitro insulin-mimetic activity among these complexes. Then, we examined the anti-diabetic effects of Zn(alx)2 complex in type 2 diabetic animals. The blood glucose lowering effects of Zn(alx)2 and Zn(ma)2 were compared, and both complexes were found to lower the high blood glucose level in type 2 diabetic KKAy mice after a 14-day course of daily i.p. injections. However, Zn(alx)2 improved glucose tolerance in KKAy mice much more than Zn(ma)2, indicating that Zn(alx)2 possesses a higher in vivo anti-diabetic activity than Zn(ma)2. In addition, Zn(alx)2 improved the leptin resistance, suppressing the progress of obesity in KKAy mice. On the basis of these observations, we propose that Zn(alx)2 complex is a novel potent candidate for the treatment of type 2 diabetes mellitus.
