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SummaryThe therapy of insulin-dependent diabetes mellitus (IDDM) is achieved only by daily subcutaneous injections of insulin, and compounds that can replace insulin or insulin-mimetics for oral administration need to be developed. Vanadate ion, vanadyl ion and their complexes have been reported to possess insulin-mimetic activities in both in vitro and in vivo experiments. On the basis of our recent preliminary finding that a bis(picolinato)oxovanadium (VO-PA) complex has a possible hypoglycemic activity when given by oral administration to streptozotocin-induced diabetic rats (STZ-rats), we synthesized several analogs of the VO-PA complex and examined the relationship between their structures and insulin-mimetic activity. Bis(methylpicolinato)oxovanadium (VO-MPA) complex, which has a relatively high partition coefficient among the prepared complexes, was found to be effective to inhibit in vitro release of free fatty acid from isolated rat adipocytes, similar to VO-PA. VO-MPA complex was thus given to STZ-rats by intraperitoneal injection or oral administration, and was found to normalize the serum glucose levels without the body weight loss. Especially, on oral administration of the complex, the normal serum glucose level was maintained for 80 days after the cessation of the complex administration. The long-acting character of the complex was suggested by the fact that vanadium is incorporated in bone as well as in kidney or other organs. Based on these observations, VO-MPA was proposed to be an useful agent not only to treat IDDM in experimental animals but to analyze the mechanism for the insulin mimetic activity of vanadium compounds.

A new vanadyl complex, bis(5-iodopicolinato)oxovanadium(IV), VO(IPA)2, with a VO(N2O2) coordination mode, was prepared by mixing 5-iodopicolinic acid and VOSO4 at pH 5, with the structure characterized by electronic absorption, IR, and EPR spectra. Introduction of the halogen atom on to the ligand enhanced the in vitro insulinomimetic activity (IC50 = 0.45 mM) compared with that of bis(picolinato)oxovanadium(IV) (IC50 = 0.59 mM). The hyperglycemia of streptozotocin-induced insulin-dependent diabetic rats was normalized when VO(IPA)2 was given by daily intraperitoneal injection. The normoglycemic effect continued for more than 14 days after the end of treatment. To understand the insulinomimetic action of VO(IPA)2, the organ distribution of vanadium and the blood disposition of vanadyl species were investigated. In diabetic rats treated with VO(IPA)2, vanadium was distributed in almost all tissues examined, especially in bone, indicating that the action of vanadium is not peripheral. Vanadyl concentrations in the blood of normal rats given VO(IPA)2 remain significantly higher and longer than those given other complexes because of its slower clearance rate. VO(IPA)2 binds with the membrane of erythrocytes, probably owing to its high hydrophobicity in addition to its binding with serum albumin. The longer residence of vanadyl species shows the higher normoglyceric effects of VO(IPA)2 among three complexes with the VO(N2O2) coordination mode. On the basis of these results, VO(IPA)2 is indicated to be a preferred agent to treat insulin-dependent diabetes mellitus in experimental animals.

Thirty sediment cores (30-40 cm in length), 47 Ekman dredge sediments, and Mn concretions were collected from Lake Biwa. The concentrations of 36 elements in the samples were determined by instrumental neutron activation, X-ray fluorescence, atomic absorption, and colorimetric analyses. The elements determined included Mn,

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