We prepared and characterized [meso-tetrakis(4-sulfonatophenyl)porphyrinato]
zinc(II) ([Zn(
tpps)]), and investigated its in vitro
insulin-mimetic activity and in vivo
hypoglycemic effect in type 2 diabetic KKA(y) mice. The results were compared with those of previously proposed
insulin-mimetic
zinc(II) complexes and
zinc sulfate (ZnSO(4)). The in vitro
insulin-mimetic activity of [Zn(
tpps)] was considerably better than that of
bis(allixinato)zinc(II) ([Zn(alx)(2)]),
bis(maltolato)zinc(II) ([Zn(mal)(2)]), bis(2-aminomethylpyridinato)zinc(II) ([Zn(2-ampy)(2)](2+)), and ZnSO(4). In particular, the order of in vitro
insulin-mimetic activity of the complexes was determined to be: [Zn(
tpps)]>[Zn(alx)(2)]>[Zn(mal)(2)]>[Zn(2-ampy)](2+)>ZnSO(4). [Zn(
tpps)] normalized the
hyperglycemia of KKA(y) mice within 21 days when administered orally at doses of 10-20 mg (0.15-0.31 mmol) Zn per kg body mass for 28 days. In addition,
metabolic syndromes such as
insulin resistance, the degree of renal disturbance, and the degree of liver disturbance were significantly improved in [Zn(
tpps)]-treated KKA(y) mice relative to those administered with saline and ZnSO(4). The improvement in diabetes was validated by the results of oral
glucose-tolerance tests and the decrease in the HbA(1c) level observed. In contrast, ZnSO(4) and the
ligand H(2)
tpps did not lower the elevated
blood glucose level under the same experimental conditions. Based on these observations, [Zn(
tpps)] is proposed to be the first orally active
zinc(II)-
porphyrin complex for the efficacious treatment of not only
type 2 diabetes but also
metabolic syndromes in animals.