A novel drug delivery system for type 1 diabetes: Insulin-mimetic vanadyl-poly(γ-glutamic acid) complex

Insulin-mimetic vanadyl-poly(γ-glutamic acid) complex, VO-γ-PGA, is proposed as a novel drug delivery system for treating type 1 diabetic animals. The structure of VO-γ-PGA in solution as well as in solid state was analyzed by electronic absorption, infra-red, and electron spin resonance spectra, and proposed that the equatorial coordination mode of VO2+ is in either carboxylate(O)–VO–(OH2)3 or 2 carboxylate(O2)–VO–(OH2)2. In vitro insulin-mimetic activity, metallokinetic feature in the blood of healthy rats, and in vivo normoglycemic effect of the complex prepared in solution were evaluated in streptozotocin(STZ)-induced type 1 diabetic mice, and these effects were compared with those of a solution containing only VOSO4 as a positive control. The in vitro insulin-mimetic activity of VO-γ-PGA was examined by determining both inhibition of free fatty acid (FFA) release and glucose uptake in isolated rat adipocytes, in which the concentration of VO-γ-PGA for 50% inhibition of FFA release was significantly lower than that of VOSO4. Metallokinetic study suggested that the bioavailability of VO-γ-PGA complex was much higher than that of VOSO4. The complex showed a significant hypoglycemic activity within at least 4 h after a single oral administration, the effect being sustained for at least 24 h. Furthermore, VO-γ-PGA normalized the hyperglycemia in STZ-mice within 3 days when it was given orally at doses of 5–10 mg V kg−1 body mass for 16 days. The improvement in diabetes was also supported by the results on oral glucose tolerance test, HbA1c levels, and blood pressure.