Department of Biochemistry
School of Medicine & Biomedical Sciences
Faculty
GAIL R. WILLSKY, Ph.D.
Associate Professor
Cellular Metabolism of Vanadium
Our main research interest is the role of oxovanadium compounds in cellular metabolism. Vanadium is a trace metal which is required for growth in algae and bacteria but can also be cytotoxic. A new twist in vanadium research has been the finding that oral administration of oxovanadium compounds alleviates the symptoms of Diabetes mellitus in animal models and humans. The mechanism of this insulin-mimetic action remains elusive at the current time. Most workers believe that the vanadium compounds inhibit a protein tyrosine phosphatase in the insulin signaling pathway. We have extended our research interest to include the insulin-like effect of other transition metals in an effort to better understand the mechanism of vanadium action in alleviating the symptoms of diabetes. Our group uses the techniques of genetics, molecular biology, biochemistry, magnetic resonance spectroscopy, and physiology (both whole animal and cell) to determine the role of oxovanadium compounds in metabolism.
The major focus of the laboratory is the use of vanadium to alleviate the symptoms of diabetes in mammalian systems. Currently, work is being finished on the pharmacokinetics of vanadium after oral administration of vanadyl sulfate in non-insulin dependent Diabetes mellitus (NIDDM) patients in collaboration with Drs. Kahn and Goldfine at the Joslin Diabetes Center in Boston, MA. Although there was a correlation of 0.99 for peak total elemental vanadium in serum and dose of vanadyl sulfate, there was no individual correlation between levels of vanadium in serum and clinical response as measured by euglycemic insulin clamp and changes in fasting blood glucose. We are also investigating the efficacy of transition-metal analogues of vanadium (synthesized by Dr. Crans' Laboratory at Colorado State University) in alleviating the symptoms of diabetes in rats with streptozotocin-induced diabetes. In addition, oxovanadium metabolism is being studied in the yeast Saccharomyces cerevisiae; these studies involve characterization of four major classes of vanadate-resistant mutants and studies of the plasma membrane vanadate-stimulated NADH oxidation activity. Preliminary work is also being done on the purification for crystallization of a dual specificity protein phosphatase (tyrosine and serine/threonine phosphorylated residues) from cyanobacteria. The long term goal of this project is understanding the specificity of vanadium inhibition of protein phosphatases involved in signal transduction pathways.
Selected Recent Publications
Smee, J.J., Epps, J.A., Ooms, K., Bolte, S.B. Polenova, T., Baruah, B.,Yang, L., Ding,W.,Li, M., Willsky, G.R., la Cour, A., Anderson, O.P., and Crans, D.C.(2009) Chloro-Substituted Dipicolinate Vanadium Complexes:Synthesis, Solution, Solid-State and Insulin Enhancing Properties, J. Inorg. Biochem. 103(4): 575-584.
Ming Li, Wenjun Ding, Jason J. Smee, Bharat Baruah, Gail R. Willsky, Debbie C. Crans (2009) Anti-diabetic effects of vanadium (III, IV, V) - chlorodipicolinate complexes in streptozotocin-induced diabetic rats. Under revision for Biometals. [PDF]
Tracey, A., Willsky, G. R., Takeuchi, E. R. (2007) Vanadium: Chemistry, Biochemistry, Pharmacology and Technical Applications, (Boca Raton FL: CRC Press) 250 pages.
Willsky, Gail R., Godzalla, Michael E. III, Kostyniak, Paul J., Chi, Lai-Har, Gupta, Rohit, Yuen, Violet G., McNeill, John H., Mahroof-Tahir, Mohammad, Smee, Jason J., Yan, Luqin, Lobernick, Aaron, Watson, Shari and Crans, Debbie C., (2007) Comparing Administration Route in Rats with Streptozicin-Induced Diabetes and Inhibition of Myoblast Growth of Vanadium [V(III), V(IV) and V(V)] Dipicolinic Acid Complexes. ACS Symposium Series 974 Vanadium 93-109.
Smee, Jason J., Epps, Jason A., Teissedre, Guillaume, Maes, Mandy, Harding, Nichola, Yang, Luqin, Baruah, Bharat, Miller, Susie M., Anderson, Oren P., Willsky, Gail R., Crans, Debbie C. (2007) 4-Amino- and 4-Nitrodipicolinatovanadium(V) Complexes and Their Hydroxylamido Derivatives: Synthesis, Aqueous, and Solid-State Properties. Inorg. Chem. 46 9827-9840.
Gail R. Willsky1, Lai-Har Chi1, Yulan Liang2, Daniel P. Gaile 2, Zihua Hu3 and Debbie C. Crans (2006) Diabetes Altered Gene Expression in Rat Skeletal Muscle Corrected by Oral Administration of Vanadyl Sulfate Physiol Genomics 26:192-201. [PDF] Supplemental: [PDF]Hu, Zihua; Willsky, Gail R.. (2006) Utilization of two sample t-test statistics from redundant probe sets to evaluate different probe set algorithms in GeneChip studies. BMC Bioinformatics 7:12 doi:10.1186/147-2105-7-12 (online journal) [PDF]
Péter Buglyó, Debbie C. Crans* Eszter M. Nagy, Ruby Lisa Lindo, Luqin Yang, Jason J. Smee,Wenzheng Jin, Lai-Har Chi, Michael E. Godzala III, and Gail R. Willsky* (2005) Aqueous Chemistry of the VanadiumIII and the VIII-Dipicolinate Systems and a Comparison of the Effect of Three Oxidation States of Vanadium Compounds on Diabetic Hyperglycemia in Rats Inorganic Chemistry 44: 5416-5427. [PDF]
Crans, D.C., Smee, J.S., Gaidamauskiene, E.G., Anderson, O.P., Miller, S.M., Jin, W., Gaidamauskas, E., Crubellier, E, Grainda R., Chi, L-H. and Willsky, G.R. (2004) Inhibition of yeast growth by molybdenumhydroxylamine coplexes correlates with their stability in media at differing pH values. J. Inorg. Biochem. 98: 1837-1850
Willsky, G. R.; Chi, L.-H. and Crans, D. C. (2003) Identification of gene expression changes in skeletal muscle from diabetic rats corrected by oral administration of vanadyl sulfate. BITREL Proceedings, in press.
Crans, D.C., Yang L.,. Alfano, J.A., Chi, Wenzheng, L.H., Mahroof-Tahir, M.J., Robbins, K., Toloue, M.M., Chan, L.K,, Plante A.J., Grayson, R.Z., and Willsky, G.R., (2003) (4-hydroxypyridine-2,6-dicarboxylato) oxovanadate(V) - A New Insulin-Like Compound: Chemistry: Effects on Myoblast and Yeast Cell Growth and Effects on Hyperglycemia in Rats with STZ-induced Diabetes.Coord. Chem. Rev. 237: 13-22.
Crans, D.C.; Yang, L.; Alfano, J.A.; Chi, L-H; Jin, W.; Mahroof-Tahir, M.; Robbins, K.; Toloue, M.M.; Chan, L.K.; Plante, A.J.; Grayson, R.Z.; and Willsky, G.R. (2003) (4-Hydroxypyridine-2,6-dicarboxylate) oxovanadate(V) - a new insulin-like compound: chemistry, effects on myoblast and yeast cell growth and effects on hyperglycemia in rats with STZ-induced diabetes. Coord. Chem. Rev. 237, 13-22.
Crans, D.C. Mahroof-Tahir, M., Johnson, M.D., Wilkins, P.C, Yang, L, Robbins, K., Johnson, A., Alfano, J.A., Godzala, III, M.E., Austin, L.D., and Willsky, G.R. (2003) Vanadium (IV) and Vanadium (V) Complexes of Dipicolinic Acid and Derivatives: Synthesis, X-ray Structure,k Solution State Properties and Effects in Rats with STZ-induced Diabetes. Inorganica Chimica Acta 356: 365-378.L. Yang, D. C. Crans,* S. M. Miller, A. la Cour, O. P. Anderson, P.M. Kaszynski, M.E. Godzala, III, L. D. Austin and G. R. Willsky. (2002) Cobalt(II) and Cobalt(III) Dipicolinate Complexes: Solid State, Solution and in vivo Insulin-like Properties. Inor. Chem. 41, 4859-71.
Yang, L., Crans, D.C. Miller, S.M, LaCour Agnete , Anderson, O.P Kaxynski, P.M, Austin, L.D., and Willsky, G.R. (2002) Cobalt(II) and Cobalt (III) dipicolinate complexes, Solid State, Solution Properties and insulin-like activity. Inor. Chem. 41, 4859-71.
Willsky, G.R., Goldfine, A.B., Kostyniak, P.J., McNeill, J.H., Yang, L.Q., Khan, H.R., and Crans, D.C.(2001) Effect of vanadium (IV) compounds in the treatment of Diabetes: in vivo and in vitro studies with vanadyl sulfate and bis(maltolato)oxovanadium (IV). J. Inorg. Biochem. 85: 33-42. [PDF]G.R. Willsky, A.B. Goldfine, P.J. Kostyniak, L.Q. Yang, H.R. Khan and D.C. Crans. (2001) Effect of vanadium (IV) compounds in the treatment of diabetes: in vivo and in vitro studies with vanadyl sulfate and Bis(maltolato)oxovanadium (IV). J. Inorg. Bioch. 85: 33-42.
Goldfine, A.B., M-E. Patti, L.Zuberi, B.J. Goldstein, R.LeBlanc, E.J.Landaker, Z.Y. Jiang, G. R. Willsky and C.R. Kahn (2000) Metabolic Effects of Vanadyl Sulfate in Humans with Non-Insulin-Dependent Diabetes Mellitus: In Vivo and In Vitro Studies. Metabolism 49: 400-410. [PDF]
A.B. Goldfine, M.-E. Patti, L. Zuberi, B.J. Goldstein, R. LeBlanc, E.J. Landaker, Z.Y. Jian, G.R. Willsky and C. R. Kahn. (2000) Metabolic effects of vanadyl sulfate in humans with non-insulin-dependent diabetes mellitus: in vivo and in vitro studies. Metabolism 49: 400-410.