title: A novel drug delivery system for type 1 diabetes: insulin-mimetic vanadyl-poly(gamma-glutamic acid) complex.
abstract: Insulin-mimetic vanadyl-poly(gamma-glutamic acid) complex, VO-gamma-PGA, is proposed as a novel drug delivery system for treating type 1 diabetic animals. The structure of VO-gamma-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 VO(2+) is in either carboxylate(O)-VO-(OH(2))(3) or 2 carboxylate(O(2))-VO-(OH(2))(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 VOSO(4) as a positive control. The in vitro insulin-mimetic activity of VO-gamma-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-gamma-PGA for 50% inhibition of FFA release was significantly lower than that of VOSO(4). Metallokinetic study suggested that the bioavailability of VO-gamma-PGA complex was much higher than that of VOSO(4). The complex showed a significant hypoglycemic activity within at least 4h after a single oral administration, the effect being sustained for at least 24h. Furthermore, VO-gamma-PGA normalized the hyperglycemia in STZ-mice within 3 days when it was given orally at doses of 5-10mgVkg(-1) body mass for 16 days. The improvement in diabetes was also supported by the results on oral glucose tolerance test, HbA(1c) levels, and blood pressure.
authors.affiliation: Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Subarna
authors.initials: S
authors.lastname: Karmaker
authors.forename: Tapan K
authors.initials: TK
authors.lastname: Saha
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshikawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasui
authors.forename: Hiromu
authors.initials: H
authors.lastname: Sakurai
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D016503:Drug Delivery Systems / Q000379:methods*; D018698:Glutamic Acid / Q000008:administration & dosage*; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007328:Insulin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D014639:Vanadium / Q000737:chemistry*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D014639:Vanadium; D018698:Glutamic Acid