Five kinds of N-substituted 3-hydroxy-2-methyl-4(1H)-pyridinones, and three kinds of 1-hydroxy-2(1H)-pyrimidinones were synthesized. Treatment of 3-hydroxy-4(1H)-pyridinones with VO(acac)₂ in CH₃OH exclusively gave CH₃O-coordinated oxovanadium (V) complexes. On the other hand, treatment with VOSO₄ in H₂O at pH 10 for 3-hydroxy-4(1H)-pyridinones and at pH 7 for 1-hydroxy-2(1H)-pyrimidinones afforded the corresponding oxovanadium (IV) complexes. These complexes were fully characterized by means of IR, UV-vis, ¹H-and ⁵¹V-NMR, FAB-MS, ESR spectroscopies, and combustion analysis. From the result of the inhibitory effect of oxovanadium (IV) complexes on free fatty acid (FFA) release from rat adipocytes treated with epinephrine in the presence of glucose in vitro, it was revealed that bis(1,2-dihydro-4,6-dimethyl-2-oxo-1-pyrimidinolato)oxovanadium (IV) showed the highest insulin-mimetic activity. Furher, the in vivo insulin-mimetic activity was evaluated with streptozotocin (STZ)-induced diabetic rats. Blood glucose levels were substantially lowered from hyperglycemic to nomal levels after the treatment with bis (1,2-dihydro-4,6-dimethyl-2-oxo-1-pyrimidinolato) oxovanadium (IV) by daily intraperitoneal injections.

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This paper argues the possible effects of natural vanadium-containing Mt. Fuji ground water on the hyperglycemia based on our previously reported animal and clinical studies. In the animal studies, we documented that the activities of liver insulin receptors, particularly β subunit, and primary insulin-like growth factor-1 β were recovered to the normal levels by the daily forced oral treatment with Mt. Fuji ground water containing natural vanadium in Goto-Kakisaki (GK) rat which is the genetic model of Type II diabetes. Furthermore the increased levels of blood glucose and serum hemoglobin A1C (HbA1C) of GK rats were significantly blocked by the consecutive treatment of natural vanadium water. It is interesting that the other genetic model of Type II diabetes, KK^Ay mice, were likely to be shown the inhibitory effects of the consecutive treatment of natural vanadium water on increases of blood glucose but not significant. In these animals, however, the significant improvements of Glut 4 transporter and receptor activities in the adipose and muscle were detected. In the clinical studies, the levels of blood glucose and serum HbA1C of hyperglycemic patients were significantly reduced by three month consecutive treatment of this Mt. Fuji ground water, and also the QOL of these patients were completely improved, although these effects were clearly affected by the changes in each life style. Thus both animal and human studies suggest that the daily treatment with Mt. Fuji ground water containing natural vanadium is useful for the regulation of blood glucose levels and the improvement of QOL to the hyperglycemia patients due to the improvements of glucose transporter and the insulin receptor and so on. However it might be little difficult to expect the significant improvement of the severe conditions of diabetes mellitus by the consecutive treatment of natural vanadium water, since this ground water is good as a supplement.

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During the investigation on the development of Zn(II) complexes with a blood glucose-lowering effect in experimental diabetic animals, we found a potent bis(maltolato)Zn(II) complex (Zn(ma)₂) which exhibited an excellent blood glucose lowering effects in a type 2 diabetic animal model by daily intraperitoneal (i.p.) injections. In order to find orally active Zn(II) complexes in treating type 2 diabetic mellitus, we examined the in vitro and in vivo structure-activity relationships of Zn(II) complexes by using bis(3-hydroxypyronato)Zn(II) complex (Zn(3hp)₂) as a leading compound. Zn(II) complex (Zn(alx)₂) with allixin (Halx) isolated from garlic, exhibited the relatively high in vitro insulin-mimetic activity, as determined by the inhibition of free fatty acid (FFA)-release in isolated rat adipocytes treated with epinephrine. The insulin-mimetic activity of Zn(II) complexes examined strongly correlated with the partition coefficient of the ligand, indicating that the activity of Zn(II) complexes depends on the lipophilicity of the ligand. In type 2 diabetic KKA^y mice, Zn(alx)₂ exhibited higher anti-diabetic activity than Zn(ma)₂ by daily i.p. injections for 2 weeks. In addition, daily oral administrations of Zn(alx)₂ lowered the high blood glucose levels in KKA^y mice, however the effect was not so high. In order to find more active Zn(II) complexes than Zn(alx)₂, three Zn(alx)₂-related complexes were newly prepared and a Zn(II) complex (Zn(tanm)₂) with 1,6-dimethyl-3-hydroxy-5-methoxy-2-pentyl-1,4-dihydropyridine-4-thionato was found to have extremely high in vitro insulin-mimetic activity.

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Zn(II) complex is known to have insulinomimetic activity at a lower concentration than the simple Zn ion. In this study, the effects of Zn(II) complex with papaya powder (papaya/Zn) were assessed in two kinds of model animals of type 2 diabetes. At first, we investigated anti-diabetic effects of papaya/Zn on KK-A^y mice. Each animal was examined for its body weight, food intake, blood glucose levels, glucose tolerance and HbA_1c levels. As results, the body weight of mice treated with papaya/Zn was significantly lower than the other diet groups after 1 week of administration. This tendency lasted till the eighth week of age. Blood glucose level also showed the same tendency. After 6 weeks, the mice treated with papaya/Zn showed significant decrease in HbA_1c level and significantly lower level of blood glucose at 0 and 180 minutes in oral glucose tolerance test. And we also investigated effects of papaya/Zn on Otsuka Long-Evans Tokushima Fatty (OLETF) rats, model animals of type 2 diabetes with obesity, and Long-Evans Tokushima Otsuka (LETO) rats as non-obese and non-diabetic controls. The oral administration of papaya/Zn during a period of 6 to 24 weeks of age did not effect on the body weights, fat deposits in abdominal cavity and abdominal subcutaneous tissues, fasting blood glucose levels, glucose tolerances, and serum triglyceride levels in both groups of rats. However, blood fluidity in OLETF rats was improved significantly compared to that of LETO rats with papaya/Zn. In addition, the level of plasma thiobarbituric acid reactive substance (TBARS), an indicator of oxidative stress, decreased significantly after administration of papaya/Zn. Thus, papaya/Zn might be a useful supplement for prevention of complications in type 2 diabetics through improving blood fluidity and reducing oxidative stress.

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