Long-Term Acting and Orally Active Vanadyl-Methylpicolinate Complex with Hypoglycemic Activity in Streptozotocin-Induced Diabetic Rats.

Abstract

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.

Insulin-Mimetic Vanadyl(IV) Complexes as Evaluated by Both Glucose-Uptake and Inhibition of Free Fatty Acids (FFA)-Release in Isolated Rat Adipocytes

“…Bis(picolinato)vanadyl (VO(pa) 2 ), and bis(6-methylpicolinato)vanadyl (VO(6mpa) 2 ) complexes were prepared as described. 37,38) Collagenase (Type II), bovine serum albumin (BSA; fraction V), and (Ϯ)-epinephrine hydrochloride (adrenaline) were obtained from Sigma Chemical (St. Louis, MO, U.S.A. 4 and 24 mM NaHCO 3 : pH 7.4) containing 2% BSA at 37°C with gentle shaking at 100 cycles/min for 1 h. At the end of the incubation, the prepared cells were filtered through sterilized cotton gauze and washed three times with KRB buffer. The cells were counted in a hemacytometer after trypan blue staining.…”

“…5,6,27) In 1995, we proposed a new in vitro assay, based on the inhibition of FFA (free fatty acids)-release from isolated rat adipocytes treated with epinephrine (adrenalin), which is simple and convenient compared with the use of RI reagents. 35) By this in vitro assay, we have evaluated some insulin-mimetic activities of vanadyl complexes with different chemical structures and coordination modes such as VO(O 4 ), 36) VO(N 2 O 2 ), [37][38][39][40][41][42][43] VO(S 2 N 2 ), 36) VO(S 2 O 2 ), 44,45) VO(N 3 O), 39) and VO(N 4 ). 28) Our results indicate that the complexes with a strong ability to inhibit FFA-release from adipocytes lowered the high blood glucose levels in type 1 and 2 diabetic animals more effectively than VOSO 4 .…”

Structural study of the interaction of vanadate with the ligand 1,2-dimethyl-3-hydroxy-4-pyridinone (Hdmpp) in aqueous solution

“…Since then, research has been undertaken to obtain insulin-mimetic vanadium compounds to be used as oral substitutes of insulin [2,3]. Bis(maltolato)oxovanadium(IV) (BMOV) seems to be a very promising drug in the control of diabetes due to its insulin-like effects [2].…”

4-Fluoro-N'-(2-hydroxy-3-methoxybenzylidene) benzohydrazide and its Oxidovanadium(V) Complex: Syntheses, Crystal Structures and Insulin-enhancing Activity

“…11,12 Yet, there are some side effects of BMOV, principally diarrhea. 13 Schiff bases play important role in biological chemistry. Several vanadium complexes derived from Schiff bases have shown to normalize blood glucose level with high efficiency and low toxicity, even at low concentration.…”