Newly synthesized vanadyl-poly(γ-glutamic acid) complex (VO-γ-PGA) with a VO(O4) coordination mode was found to have potent antidiabetic activity in streptozotocin (STZ)-induced type 1 diabetic mice (STZ-mice), compared with that of a solution containing only vanadyl sulfate, VOSO 4. This was the first example of orally active vanadyl complex of γ-PGA for treating STZ-mice. To better define its efficacy, we examined here the effects of VO-γ-PGA treatment in STZ-mice by oral administration at the dose of 10 mg V/kg body mass for a longer period time than our previous study. The improvement in diabetic states in STZ-mice compared with saline-treated nondiabetic normal Std ddY mice. It was found that the elevated blood glucose levels in STZ-mice significantly decreased after 3 days and sustained the normalized blood glucose level around 180—200 mg/dL (10—11.1 mM) for the last 14 days, which is close to the blood glucose levels 100—200 mg/dL (5.6—11.1 mM) in nondiabetic normal Std ddY mice. The improvement in diabetes was strongly corelated by the improvement in oral glucose tolerance ability, glycosylated hemoglobin (HbA1c) levels and blood pressure, and serum parameters. The present results confirmed that VO-γ-PGA complex is a promising, orally active insulin-mimetic agent to treat type 1 diabetic mice.
Chasteen, N.D. (ed.) (1995). Vanadium in Biological Systems, Kluwer Academic Publishers , Dordrecht, The Netherlands.
2.
Becker, D.J., Ongemba, L.N. and Henquin, J.C. (1994). Comparison of the Effects of Various Vanadium Salts on Glucose Homeostasis in Streptozotocin-Diabetic Rats, Eur. J. Pharmacol., 260: 169—175.
3.
Srivastava, A.K. and Mehdi, M.Z. (2005). Insulino-Mimetic and AntiDiabetic Effects of Vanadium Compounds, Diabet. Med., 22: 2—13.
4.
Mehdi, M.Z., Pandey, S.K., Theberge, J.F. and Srivastava, A.K. (2006). Insulin Signal Mimicry as a Mechanism for the Insulin-like Effects of Vanadium, Cell Biochem. Biophys., 44: 73—81.
5.
Mehdi, M.Z., Vardatsikos, G., Pandey, S.K. and Srivastava, A.K. (2006). Involvement of Insulin-Like Growth Factor Type 1 Receptor and Protein Kinase Cδ in Bis(Maltolato)Oxovanadium(IV)-Induced Phosphorylation of Protein Kinase B in HepG2 Cells, Biochemistry , 45: 11605—11615.
6.
Brichard, S.M. and Henquin, J.C. (1995). The Role of Vanadium in the Management of Diabetes, Trends Pharmacol. Sci., 16: 265—270.
7.
Tsiani, E. and Fantus, I.G. (1997). Vanadium Compounds: Biological Actions and Potential as Pharmacological Agents, Trends Endocrinol. Metab., 8: 51—58.
8.
Shibuichi, I. , Yasue, M., Kato, K. and Watanabe, Y. (2006). Consideration on the Effects of Natural Water Containing Vanadium on Diabetic Mellitus, Biomed. Res. Trace. Elements, 17: 11—16.
9.
Cusi, K., Cukier, S., Defronzo, R.A., Torres, M., Puchulu, F.M. and Redondo, J.C.P. (2001). Vanadyl Sulfate Improves Hepatic and Muscle Insulin Sensitivity in Type 2 Diabetes, J. Clin. Endocrinol. Metab ., 86: 1410—1417.
10.
Goldfine, A.B. , Simonson, D.C., Folli, F., Patti, M.E. and Khan, C.R. (1995). Metabolic Effects of Sodium Metavanadate in Humans with Insulin-Dependent and Noninsulin-Dependent Diabetes Mellitus In Vivo and In Vitro Studies, J. Clin. Endocrinol. Metab., 80: 3311—3320.
11.
Cazarolli, L.H., Zanatta, L., Jorge, A.P., de Sousa, E., Horst, H., Woehl, V.M., Pizzolatti, M.G., Szpoganicz, B. and Silva, F.R.M.B. (2006). Follow-Up Studies on Glycosylated Flavonoids and their Complexes with Vanadium: Their Anti-Hyperglycemic Potential Role in Diabetes, Chem. Biol. Interact., 163: 177—191.
12.
Sakurai, H. , Fugono, J. and Yasui, H. (2004). Pharmacokinetic Study and Trial for Preparation of Enteric-Coated Capsule Containing Insulinomimetic Vanadyl Compounds: Implications for Clinical Use, MiniRev. in Med. Chem., 4: 41—48.
13.
Thompson, K.H. and Orvig, C. (2004). Vanadium Compounds in the Treatment of Diabetes, Met. Ions Biol. Syst., 41: 221—252.
14.
Schechter, Y. , Goldwaser, I., Mironchik, M., Fridkin, M. and Gefel, D. (2003). Historic Perspective and Recent Developments on the Insulin-Like Actions of Vanadium; Toward Developing Vanadium-Based Drugs for Diabetes, Coord. Chem. Rev., 237: 3—11.
15.
Crans, D.C., Smee, J.J., Gaidamauskas, E. and Yang, L. (2004). The Chemistry and Biochemistry of Vanadium and the Biological Activities Exerted by Vanadium Compounds, Chem. Rev., 104: 849—902.
16.
Saha, T.K., Yoshikawa, Y., Yasui, H. and Sakurai, H. (2006). Oxovanadium(IV)-Porphyrin Complex as a Potent Insulin-Mimetic: Treatment of Experimental Type 1 Diabetic Mice by [Meso-Tetrakis(4-Sulfonatophenyl)Porphyrinato]Oxovanadate(IV)(4—) Complex, Bull. Chem. Soc. Jpn., 79: 1191—1200.
17.
Sakurai, H., Kojima, Y., Yoshikawa, Y., Kawabe, K. and Yasui, H. (2002). Antidiabetic Vanadium(IV) and Zinc(II) Complexes, Coord. Chem. Rev., 226: 187—198.
18.
Haratake, M. , Fukunaga, M., Ono, M. and Nakayama, M. (2005). Synthesis of Vanadium(IV,V) Hydroxamic Acid Complexes and In Vivo Assessment of their Insulin-Like Activity , J. Biol. Inorg. Chem., 10: 250—258.
19.
Thomson, K.H. , McNeill, J.H. and Orvig, C. (1999). Vanadium Compounds as Insulin Mimics, Chem. Rev., 99: 2561—2571.
20.
Thompson, K.H. , Liboiron, B.D., Sun, Y., Bellman, K.D.D., Setyawati, I.A., Patrick, B.O., Karunaratne, V., Rawji, G., Wheeler, J., Sutton, K., Bhanot, S., Cassidy, C., McNeill, J.H., Yuen, V.G. and Orvig, C. (2003). Preparation and Characterization of Vanadyl Complexes with Bidentate Maltol-Type Ligands; In Vivo Comparisons of Anti-Diabetic Therapeutic Potential, J. Biol. Inorg. Chem., 8: 66—74.
21.
Monga, V., Thompson, K.H., Yuen, V.G., Sharma, V., Patrick, B.O., McNeill, J.H. and Orvig, C. (2005). Vanadium Complexes with Mixed O,S Anionic Ligands Derived from Maltol: Synthesis, Characterization, and Biological Studies, Inorg. Chem., 44: 2678—2688.
22.
Karmaker, S. , Saha, T.K., Yoshikawa, Y., Yasui, H. and Sakurai, H. (2006). A Novel Drug Delivery System for Type 1 Diabetes: Insulin-Mimetic Vanadyl-Poly(γ-Glutamic Acid) Complex, J. Inog. Biochem., 100: 1535—1546.
23.
Oppermann-Saino, F.B. and Steinbuchel , A. (2002). Occurrence, Functions and Biosynthesis of Polyamides in Microorganisms and Biotechnological Production, Naturwissenschaften, 89: 11—22.
24.
Sung, M.H., Park, C., Kim, C.J., Poo, H., Soda, K. and Ashiuchi, M. (2005). Natural and Edible Biopolymer Poly-γ-Glutamic Acid: Synthesis, Production, and Applications, Chem. Rec., 5: 352—366.
25.
Burwell, E.L. , Brickley, B.A. and Finch, C.A. (1953). Erythrocyte Life Span in Small Animals, Comparison of Two Methods Employing Radioiron, Amer. J. Physiol., 172: 718—728.
26.
Koenig, R.J. , Peterson, C.M., Kilo, C., Cerami, A. and Williamson, J.R. (1976). Hemoglobin AIc as an Indicator of the Degree of Glucose Intolerance in Diabetes, Diabetes, 25: 230—232.
27.
Goldstein, D.E. , Little, R.R., Lorenz, R.A., Malone, J.I., Nathan, D., Peterson, C.M. and Sacks, D.B. (2004). Tests of Glycemia in Diabetes, Diabetes Care, 27: 1761—1773.
28.
Hansen, T.V., Aaseth, J. and Alexander, J. (1982). The Effect of Chelating Agents on Vanadium Distribution in the Rat Body and on Uptake by Human Erythrocytes, Arch. Toxicol., 50: 195—202.
29.
Jandhyala, B.S. and Hom, G.J. (1983). Minireview: Physiological and Pharmacological Properties of Vanadium, Life Sci., 33: 1325—1340.
