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

The 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.