Anti-Diabetic Effect of Organo-Chalcogen (Sulfur and Selenium) Zinc Complexes with Hydroxy-Pyrone Derivatives on Leptin-Deficient Type 2 Diabetes Model ob/ob Mice

Since the discovery of the anti-diabetic effects of zinc (Zn) complex, we synthesized several Zn complexes and evaluated their effects using the KKA(y) type 2 diabetes mouse model. Recently, we demonstrated that organo-chalcogen (sulfur and selenium) Zn complexes elicit strong anti-diabetic effects. In this study, we treated leptin-deficient ob/ob mice with organo-chalcogen Zn complexes, and evaluated the resulting anti-diabetic effects in a mouse model of diabetes arising from pathogenic mechanisms different from those in KKA(y) mice. C57BL/6J ob/ob mice orally received either bis(3-hydroxy-2-methyl-4(H)-pyran-4-thiono)Zn, [Zn(hmpt)(2)] or bis(3-hydroxy-2-methyl-4(H)-pyran-4-seleno)Zn, [Zn(hmps)(2)], daily for 28 days. Both Zn complexes elicited potent blood glucose-lowering effects and improved HbA1c values. Moreover, glucose intolerance improved as evidenced by the oral glucose tolerance test, and fasting plasma insulin levels decreased in both types of Zn complex-treated mice. Zn concentrations in the liver and pancreas of [Zn(hmpt)(2)]-treated mice and in the pancreas of [Zn(hmps)(2)]-treated mice were increased, respectively. The results suggest that the present Zn complexes mainly exerted an anti-diabetic effect in the liver or pancreas. This study is the first to demonstrate that potent Zn complexes elicit anti-diabetic effects in not only KKA(y) but also ob/ob mice via a normalizing effect on insulin secretion and fasting blood glucose levels.