IntroductionAccording to the World Health Organization’s prediction in 2006, the number of type 2 diabetic patients in the world could increase to 360 million by 2030.1The goal of diabetes treatment is to control the blood glucose levels, body weight, blood pressure, and cholesterol and triglyceride levels, and prevent the development of complications.2Combinations of alimentotherapy, ergotherapy, oral antidiabetic medicines, and/or insulin have been used to treat diabetes mellitus. Among the oral antidiabetic medicines, α-glucosidase inhibitors inhibit α-glucosidase, which metabolizes disaccharides into monosaccharides in the small intestine. The inhibition of α-glucosidase delays the digestion and absorption of carbohydrates, resulting in suppression of postprandial hyperglycemia and excessive insulin secretion. Thus, α-glucosidase inhibitors lower the insulin requirement resulting from less absorption of glucose, and lead to less strain on pancreatic β-cells in insulin production. Hyperinsulinemia is considered as a potential risk factor for arteriosclerosis. Reduced requirement for insulin secretion can reduce the risk of arteriosclerosis.3α-Glucosidase inhibitors including acarbose,4–7voglibose,8,9and miglitol10–13have been available for clinical use since 2005 (Fig. 1). Such α-glucosidase inhibitors have been approved not only as medicines but also as a food for specified health uses (FOSHU), that is available without prescription.14–16Structures of clinically used α-glucosidase inhibitors.Several metal ions and their complexes exhibit antidiabetic effects.17–22A chromium-containing material extracted from pig spleen improved glucose tolerancein vivo.17Manganese plays an important role in glucose metabolism.18Zinc exerts an insulin-like effect in rat adipocytes.19In addition, some metal ions, such as tungsten,23vanadium,24and selenium25lower high blood glucose levels in the diabetic state. It appears attractive to many researchers to study the relationship between diabetes mellitus and metal ions. The action mechanism of these metal ions, however, remains unclear. We have examined the mechanism of some transition metal ions and their complexes since 2006 and demonstrated that they activate the insulin signaling pathway followed by glucose transporter 4 (GLUT4) translocation to the plasma membrane and the enhancement of glucose utilization.26–29Furthermore, in 2004, it was reported that insulin/C-peptide were closely associated with metal ions.30In this study, we have focused on the inhibitory activity of these metals on α-glucosidase to analyze alternative action mechanisms of these metal ions. We have evaluated the α-glucosidase inhibitory activity of several divalent first-row transition metal ions, whose antidiabetic effects have been reported, such as vanadium, manganese, iron, cobalt, nickel, and copper, and a non-transition metal ion, zinc,24,31,32together with divalent alkaline earth metal ions such as magnesium, calcium, strontium, and barium.33In addition, we have compared their inhibitory activities with α-glucosidase inhibitor, acarbose, used for clinical purposes in bothin vitroandin vivoexperimental systems, and then evaluated the mode of α-glucosidase inhibition.